WO2026052743A1

WO2026052743A1 - Reduction of trans-epidermal water loss by a polypeptide with antibacterial properties

Info

Publication number: WO2026052743A1
Application number: PCT/EP2025/075241
Authority: WO
Inventors: Floortje Liselotte PIETERSMA; Vincent DE JONG
Original assignee: Micreos Human Health BV
Current assignee: Micreos Human Health BV
Priority date: 2024-09-04
Filing date: 2025-09-04
Publication date: 2026-03-12
Anticipated expiration: 2027-03-04

Abstract

The present invention relates to reduction of trans-epidermal water loss in a subject.

Description

Reduction of trans-epidermal water loss by a polypeptide with antibacterial properties

Field of the invention

Background of the invention

Trans-epidermal water loss (TEWL) is the loss of water that passes from inside a body (animal or plant) through the epidermis (that is, either the epidermal layer of animal skin or the epidermal layer of plants) to the surrounding atmosphere via diffusion and evaporation processes. TEWL in mammals is also known as insensible water loss (IWL), as it is a process over which organisms have little physiologic control and of which they are usually mostly unaware. Insensible loss of body water can threaten fluid balance; in humans, substantial dehydration sometimes occurs before a person realizes what is happening. TEWL is an objective measurement of skin integrity measured as the amount of water lost across the stratum corneum. TEWL varies greatly across variables such as age and anatomic location, and disruptions in the skin barrier have been linked to inflammatory dermatoses such as psoriasis and atopic dermatitis. TEWL is, as said, a measurement that represents the amount of water that escapes from the stratum corneum per area of skin and has historically been used as a reflection of skin water barrier integrity. TEWL measurements are typically made by placing a probe at the surface of the skin that is able to measure any changes in water vapour density across a determined area of skin over time by sensing changes in local humidity above ambient humidity values. Disruptions in the skin barrier have been linked to increased TEWL values in dermatologic diseases such as psoriasis and atopic dermatitis (Green et al, 2022).

From a clinical standpoint, TEWL measurements are of great importance in evaluating skin barrier functionality (Goia et al, 2002). Often normal rates of TEWL - from 2.3 g/(m²h) to 44 g/(m²h)(Kottner et al, 2013), more typically between 10 and 30 g/(m²h) - are compromised due to injury, infection and/or severe damage as in the case of burns causing rates over 50 or even over 100 g/m²/h (Gardien et al, 2016). Damage to the stratum corneum and superficial skin layers not only results in physical vulnerability, but also results in an excess rate of water loss. Therefore, dehydration, metabolic acidosis, and conditions such as anhydremia or concentration of the blood are often critical issues for healthcare providers to consider in the treatment of burn patients (Underhill et al, 1927; Artz et al, 1955).

TEWL is of major concern in public health, considering the relatively high rate of burn incidence among communities in the developing world due to poor quality cooking stoves (Ahuja et al, 2004). Resources for burn care in local clinics are often scarce and depending on the affected surface area, TEWL is a major issue that can be overlooked. Furthermore, TEWL is also affected by variations in sweat gland activity, temperature, and metabolism (Chilcott et al, 2002). Therefore, TWEL becomes a significant factor in dehydration associated with several major disease states. Accordingly, there is an ongoing need for the provision of novel means to reduce TWEL. Summary of the invention

The present invention relates to a method of treatment to reduce trans epidermal water loss (TEWL) from a subject by administration of a compound targeting a bacterial cell to the subject.

The invention further relates to a method of treatment to reduce TEWL from a subject by administration of a composition comprising a compound targeting a bacterial cell to the subject.

Description of the invention

The inventors have established that the administration to a subject of a polypeptide with antibacterial properties surprisingly reduces trans epidermal water loss (TEWL).

Accordingly, in a first aspect, there is provided for a compound targeting a bacterial cell for use in the reduction of trans epidermal water loss (TEWL) from a subject by administration of the compound to the subject.

In the embodiments herein, “the compound targeting a bacterial cell” is referred to as “the compound according to the invention” or plainly “the compound”. In the embodiments herein, the term “trans epidermal water loss” is abbreviated as “TEWL” and is to be construed as in the context know to the person skilled in the art, preferably as set forth in the Background section hereinabove. TEWL can be measured by any method known to the person skilled in the art, but is preferably assessed non- invasively by use of an AquaFlux AF200 system (Biox, London, UK) according to the standard operating procedure of the Centre for Human Drug Research (CHDR). A circular area of 7mm diameter of skin is enclosed by the measuring probe. The flux of water that enters the chamber is measured until a steadystate flux is reached. Measurement time is at least 90 seconds and at most 200 seconds. All measurements are performed under standard environmental conditions (temperature is 22°C ±2°C; relative humidity <60%), and subjects are acclimatized under relaxed conditions for at least 15 minutes prior to testing. Two sites are measured: the lesional skin and the non-lesional skin. In the embodiments herein, the subject is an animal subject, so flora is excluded. For the avoidance of doubt, an animal subject includes a mammal such as a human.

The person skilled in the art will comprehend that the compound can be administered as such, but can also be administered within a composition comprising the compound. Accordingly, there is also provided for a composition comprising a compound targeting a bacterial cell for use in the reduction of TEWL from a subject by administration of the composition to the subject.

The compound may comprise at least one cell wall binding domain specifically binding the peptidoglycan cell wall of said bacterial cell. In the embodiments herein, the cell wall binding domain is a moiety that directs the compound to the wall of the bacterial cell. In the embodiments herein, the cell wall-binding domain may be any cell wall-binding domain known by the person skilled in the art. A preferred cell wall binding domain may originate from or may be a homologue of a cell wall binding domain of a bacteriophage endolysin or of a bacterial lysin. In the embodiments herein, the cell wall binding domain may originate from or may be a homologue of a cell wall binding domain from a endolysin from a bacteriophage or a bacterial lysin that targets a Staphylococcus, preferably a Staphylococcus aureus or a Staphylococcus epidermidis. Preferably, said homologue may have at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with the cell wall binding domain it originates from. A preferred cell wall binding domain is one that has at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with the sequence of a cell wall binding domain as set forth in SEQ ID NO: 84, 85, 93 or 94. The person skilled in the art will comprehend that the compound may comprise one, two or more cell wall binding domains as defined herein.

In the embodiments herein, the compound may comprise one or more enzymatic active domains exhibiting specificity for an essential bond in the peptidoglycan layer of said bacterial cell. In the embodiments herein, such enzymatic active domain may be a domain that has peptidoglycan hydrolase activity, which is herein also referred to as lytic activity. An essential bond in a peptidoglycan layer of a bacterial cell is defined herein as a linkage within said peptidoglycan that is essential for said peptidoglycan to provide said bacterial cell shape and a rigid structure resistance to osmotic shock. Examples of an essential bond in the peptidoglycan layer of a bacterial cell within the context of the invention are, but are not limited to, a bond between a D-alanine of the stem peptide and a glycine of the cross-bridge peptide (defined herein also as a bond between an N-terminal alanine and a glycine), a bond in a pentaglycin cross-bridge (defined herein also as a pentaglycin bridge glycyl-glycyl bond, a bond between an N-acetylmuramoyl and an L-alanine or a bond between an N-acetylmuramine and a N-acetylglucosamine or between a N-acetlyglucosamine and an N-acetylmuramine. Other examples of essential bonds in a peptidoglycan layer a bond in a gamma-glutamyl stem peptide, a bond between an L-alanyl-iso-D-glutamic acid in a stem peptide and a bond between an iso-D-glutamic acid-L-Lysine in a stem peptide. In the embodiments herein, the enzymatic active domain may be a cysteine, histidine dependent amidohydrolase/peptidase (CHAP) domain, an endopeptidase domain, an amidase domain or a glycosylhydrolase domain. In the embodiments herein, the enzymatic active domain may originate from or may be a homologue of an enzymatic active domain of a bacteriophage endolysin or of a bacterial lysin. In the embodiments herein, the cell enzymatic active domain may originate from or may be a homologue of an enzymatic active domain from an endolysin from a bacteriophage or a bacterial lysin that targets a Staphylococcus, preferably a Staphylococcus aureus or a Staphylococcus epidermidis. Preferably, said homologue has at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with the enzymatic active domain it originates from. A preferred enzymatic active domain is one that has at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with the sequence of an enzymatically active domain as set forth in SEQ ID NO: 82, 83, 86 - 92, 95.

The person skilled in the art will comprehend that the compound may comprise one, two or more enzymatic active domains as defined herein.

In the embodiments herein, the compound may originate from or may be a homologue of a bacteriophage endolysin or of a bacterial lysin. In the embodiments herein, the compound may originate from or may be a homologue of a bacteriophage endolysin or of a bacterial lysin that targets a Staphylococcus, preferably a Staphylococcus aureus or a Staphylococcus epidermidis. Preferably, said homologue has at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with the bacteriophage endolysin or bacterial lysin it originates from.

In the embodiments herein, the compound may be any bacterial lysin or autolysin, such as AltA from Enterococcus faecalis (Mesnage et al., 2008) or Acm A, Acm B, Acm C, and Acm D from Lactococcus lactis (Steen et al, 2005).

In the embodiments herein, the compound may be any endolysin such as a bacteriophage lysin, also referred to as endolysin. Bacteriophage lysins are known to the person skilled in the art, see e.g. Bacteriophage endolysins as novel antimicrobials. Schmelcher M, Donovan DM, Loessner MJ. Future Microbiol. 2012 Oct;7(10): I 147-7.

In the embodiments herein, the endolysin may be, but is not limited to: PhiV10p30 of phage OV10 (Sequence analysis of Escherichia coll 0157:H7 bacteriophage PhiVIO and identification of a phage- encoded immunity protein that modifies the 0157 antigen. Perry LL, SanMiguel P, Minocha U, Terekhov Al, Shroyer ML, Farris LA, Bright N, Reuhs BL, Applegate BM. FEMS Microbiol Lett. 2009 Mar;292(2):182- 6); STM0907.FelsO of phage FELS-1 (Nature. 2001 Oct 25;413(6858):852-6. Complete genome sequence of Salmonella enterica serovar Typhimurium LT2. McClelland Ml, Sanderson KE, Spieth J, Clifton SW, Latreille P, Courtney L, Porwollik S, Ali J, Dante M, Du F, Hou S, Layman D, Leonard S, Nguyen C, Scott K, Holmes A, Grewal N, Mulvaney E, Ryan E, Sun H, Florea L, Miller W, Stoneking T, Nhan M, Waterston R, Wilson RK); epsilonl5p25 of phage s15 (Virology. 2007 Dec 20;369(2):234-44. Epub 2007 Sep 7. The genome of epsilonl5, a serotype-converting, Group El Salmonella enterica-specific bacteriophage. Kropinski AMI, Kovalyova IV, Billington SJ, Patrick AN, Butts BD, Guichard JA, Pitcher TJ, Guthrie CC, Sydlaske AD, Barnhill LM, Havens KA, Day KR, Falk DR, McConnell MR); YuA20 of phage YUA (NCBI Reference Sequence: YP 001595885.1 and J Bacteriol. 2008 Feb;190(4): 1429-35. The genome and structural proteome of YuA, a new Pseudomonas aeruginosa phage resembling M6. Ceyssens PJ1 , Mesyanzhinov V, Sykilinda N, Briers Y, Roucourt B, Lavigne R, Robben J, Domashin A, Miroshnikov K, Volckaert G, Hertveldt K); ORF23 of phage B3 (Complete genomic sequence of bacteriophage B3, a Mu-like phage of Pseudomonas aeruginosa. Braid MD, Silhavy JL, Kitts CL, Cano RJ, Howe MM. J Bacteriol. 2004 Oct;186(19):6560- 74); BcepMu22 of phage BcepMu (J Mol Biol. 2004 Jun 25;340(l):49-65. Burkholderia cenocepacia phage BcepMu and a family of Mu-like phages encoding potential pathogenesis factors. Summer EJ1 , Gonzalez CF, Carlisle T, Mebane LM, Cass AM, Sawa CG, LiPuma J, Young R); F116p62 of phage Fl 16 (Gene. 2005 Feb 14;346: 187-94. The genome of the Pseudomonas aeruginosa generalized transducing bacteriophage Fl 16. Byrne Ml, Kropinski AM.); STM2715.S.Fels2 of phage Fels2 (Nature. 2001 Oct 25;413(6858):852-6. Complete genome sequence of Salmonella enterica serovar Typhimurium LT2. McClelland Ml, Sanderson KE, Spieth J, Clifton SW, Latreille P, Courtney L, Porwollik S, Ali J, Dante M, Du F, Hou S, Layman D, Leonard S, Nguyen C, Scott K, Holmes A, Grewal N, Mulvaney E, Ryan E, Sun H, Florea L, Miller W, Stoneking T, Nhan M, Waterston R, Wilson RK); gp76 of phage ESI 8 (Casjens.S.R., Gilcrease.E.B., Winn-Stapley,D.A., Schicklmaier.P, Schmieger.H., Pedulla.M.L., Ford.M.E., HoutzJ.M., Hatfull, G.F. and Hendrix, R.W. The generalized transducing Salmonella bacteriophage ESI 8: complete genome sequence and DNA packaging strategy J. Bacteriol. 187 (3), 1091-1104 (2005)); SPSV3_gp23 of phage SETP3 (J Med Microbiol. 2009 Jan;58(Pt l):86-93. Characterization of bacteriophages used in the Salmonella enterica serovar Enteritidis phage-typing scheme. De Lappe Nl, Doran G, O'Connor J, O'Hare C, Cormican M); phi32_17 of phage OEC032 (Genomic and proteomic analysis of phiEco32, a novel Escherichia coll bacteriophage. Savalia D, Westblade LF, Goel M, Florens L, Kemp P, Akulenko N, Pavlova O, Padovan JC, Chait BT, Washburn MP, Ackermann HW, Mushegian A, Gabisonia T, Molineux I, Severinov K. J Mol Biol. 2008 Mar 28;377(3):774-89); HK022p54 of phage HK022 (J Mol Biol. 2000 May 26;299(1):27-51 . Genomic sequences of bacteriophages HK97 and HK022: pervasive genetic mosaicism in the lambdoid bacteriophages. Juhala RJ1 , Ford ME, Duda RL, Youlton A, Hatfull GF, Hendrix RW); HK97p58 of phage HK97 (J Mol Biol. 2000 May 26;299(1):27-51 . Genomic sequences of bacteriophages HK97 and HK022: pervasive genetic mosaicism in the lambdoid bacteriophages. Juhala R JI, Ford ME, Duda RL, Youlton A, Hatfull GF, Hendrix RW); HK620p36 of phage HK620 (Nucleotide sequence of coliphage HK620 and the evolution of lambdoid phages. Clark AJ, Inwood W, Cloutier T, Dhillon TS. J Mol Biol. 2001 Aug 24;311 (4):657-79); VIP0007 of phage El (Molecular characterization of the Salmonella enterica serovar Typhi Vi-typing bacteriophage El . Pickard D, Thomson NR, Baker S, Wain J, Pardo M, Goulding D, Hamlin N, Choudhary J, Threfall J, Dougan G. J Bacteriol. 2008 Apr; 190(7) :2580-7); Sf6p62 of phage SF6 (J Mol Biol. 2004 May 28;339(2):379-94. The chromosome of Shigella flexneri bacteriophage Sf6: complete nucleotide sequence, genetic mosaicism, and DNA packaging. Casjens SI, Winn-Stapley DA, Gilcrease EB, Morona R, Kuhlewein C, Chua JE, Manning PA, Inwood W, Clark AJ); R (SfVp40) of phage SFV (J Bacteriol. 2002 Apr; 184(7): 1974-87. Complete genomic sequence of SfV, a serotypeconverting temperate bacteriophage of Shigella flexneri. Allison GE1 , Angeles D, Tran-Dinh N, Verma NK); gp22 of phage BCEPC6B (Summer, E.J., Christian, B.N., Collins, J., Morrison, W, Patel, P, Wells, W, Mebane, L., Gonzalez, C.E and Young, R.E GenBank: AAT38381.1); Nazgul38 of phage BCEPNAZGUL (Summer, E. J., Peek.M.L., HaliburtonJ.R., Hall.E., Heusinkveld.K., SimserJ., No,E.G., Gonzalez, C.F. and Young, R.E NCBI Reference Sequence: NP 918971.2); K (P2p09) of phage P2 (Christie, G.E., Haggard- Ljungquist.E. and Calendar, R. NCBI Reference Sequence: NP 046765.1); K (Wphi09) of phage WO (Esposito, D., Schmidt, B.J., Bloom, F.R. and Christie, G.E. GenBank: AAN28227.1); rv5_gp085 of phage RV5 (Virol J. 2013 Mar 6;10:76. The host-range, genomics and proteomics of Escherichia coll 0157:H7 bacteriophage rV5. Kropinski AMI, Waddell T, Meng J, Franklin K, Ackermann HW, Ahmed R, Mazzocco A, Yates J 3rd, Lingohr EJ, Johnson RP); EpJS98_gpl 16 of phage JS98 (Zuber, S., Ngom-Bru,C, Barretto.C, Bruttin.A., Brussow, H. and Denou.E. Genome analysis of phage JS98 defines a fourth major subgroup of T4-like phages in Escherichia coll J. Bacteriol. 189 (22), 8206-8214 (2007)); gp3.5 of phage 13A (Savalia, D., Severinov, K. and Molineux,!. NCBI Reference Sequence: YP 002003950.1); gp3.5 of phage BAM (Savalia, D., Severinov, K. and Molineux.l. GenBank: ACF15743.1); gp3.5 of phage ECODS1 (Savalia, D., Severinov, K. and Molineux.l. GenBank: ACF15800.1); CKVIF_gpl6 of phage K1 F (Scholl, D. and Merril.C. The Genome of Bacteriophage K1 F, a T7-Like Phage That Has Acquired the Ability To Replicate on KI Strains of Escherichia coli . Bacterid. 187 (24), 8499-8503 (2005)); T3pl8 of phage T3 (Pajunen.M.L, Elizondo, M.R., Skurnik.M., KieleczawaJ. and MolineuxJ.J. Complete nucleotide sequence and likely recombinatorial origin of bacteriophage T3 J. Mol. Biol. 319 (5), 1115-1132); gh-lpl2 of phage GH-1 (Kovalyovai.V. and Kropinski.A.M. The complete genomic sequence of lytic bacteriophage gh-1 infecting Pseudomonas putida — evidence for close relationship to the T7 group Virology 311 (2), 305-315 (2003)); gp3.5 of phage KI I (Savalia.D., Severinov.K. and Molineux.l. NCBI Reference Sequence: YP 002003804.1); ORF12 of phage OCTX (Nakayama, K., Kanaya.S., Ohnishi.M., Terawaki.Y. and Hayashi, T. The complete nucleotide sequence of phi CTX, a cytotoxin-converting phage of Pseudomonas aeruginosa-, implications for phage evolution and horizontal gene transfer via bacteriophages Mol. Microbiol. 31 (2), 399-419 (1999)); Bcep43-27 of phage BCEP43 (Summer, E.J., Gonzalez, C.F., Borner, M., Carlile, T., Embry, A., Kucherka.A.M., Lee, J., Mebane, L., Morrison, W.C., Mark,L., King.M.D., LiPumaJ.J., Vidaver, A. K. and Young, R. Divergence and mosaicism among virulent soil phages of the Burkholderia cepacia complex J. Bacteriol. 188 (1), 255-268 (2006)); Bcep781-27 of phage BCEP781 (Summer, E. J., Gonzalez, C.F., Borner, M., Carlile, T., Embry, A., Kucherka.A.M., Lee, J., Mebane, L., Morrison, W.C., Mark.L., King.M.D., LiPumaJ.J., Vidaver, A. K. and Young, R. Divergence and mosaicism among virulent soil phages of the Burkholderia cepacia complex J. Bacteriol. 188 (1), 255- 268 (2006)); Bcepl-28 of phage BCEP1 (Summer, E.J., Gonzalez, C.F., Borner, M., Carlile, T., Embry, A., Kucherka.A.M., Lee, J., Mebane, L., Morrison, W.C, Mark.L., King.M.D., LiPumaJ.J., Vidaver, A.K. and Young, R. Divergence and mosaicism among virulent soil phages of the Burkholderia cepacia complex J. Bacteriol. 188 (1), 255-268 (2006)); BcepNY3gene26 of phage BCEPNY3 (GenBank: ABR10561.1 Summer, E. J., Orchard, R.C, Attenhofer.K., Coffey, A., GillJ.J., Gonzalez, C.E and Young, R.); gp45 of phage <t>E12-2 (NCBI Reference Sequence: YP 001111195.1 DeShazer.D., Ronning.C.M., Brinkac.L.M. and Merman, W.C.); gp28 of phage <t>52237 (DeShazer, D and Merman, W.C. NCBI Reference Sequence: YP 293741.1 DeShazer.D., Ronning.C.M., Brinkac.L.M. and Merman, W.C); P27p30 of phage <t>P27 (RecktenwaldJ. and Schmidt, H. The nucleotide sequence of Shiga toxin (Stx) 2e-encoding phage phiP27 is not related to other Stx phage genomes, but the modular genetic structure is conserved Infect. Immun. 70 (4), 1896-1908 (2002)); RB49plO2 of phage RB49 (Monod.C, Repoila.F., Kutateladze, M., Tetart.F. and Krisch.H.M. The genome of the pseudo T-even bacteriophages, a diverse group that resembles T4 J. Mol. Biol. 267 (2), 237-249 (1997)); phil-pl02 of phage 4>1 (Arbiol.C, Comeau, A.M., Kutateladze, M., Adamia.R. and Krisch.H.M. Mobile regulatory cassettes mediate modular shuffling in t4-type phage genomes Genome Biol Evol 2010, 140-152 (2010)); lys (T5.040) of phage T5 (NCBI Reference Sequence: YP 006868.1 Ksenzenko.V.N., Kaliman, A.V, Krutilina.A. I. and Shlyapnikov.M.G.); YP 001956952.1 of phage 201 phi2-l (ThomasJ.A., Rolando, M.R., Carroll, C.A., Shen.P.S., Belnap.D.M., Weintraub, S.T., Serwer.P. and Hardies, S.C. Characterization of Pseudomonas chlororaphis myo virus 201varphi2-l via genomic sequencing, mass spectrometry, and electron microscopy Virology 376 (2), 330-338 (2008)); Aehlp339 of phage Aehl (NCBI Reference Sequence: NP 944217.1 Petrov, V, NolanJ., Bertrand, C, Letarov.A.V, Krisch.H.M. and KaramJ.D); YYZgp45 of phage YYZ-2008 (GenBank: ACI32381.1 Zhang, Y, Laing, C.R., Kropinski.A. and Gannon, V.J.P.); the endolysin ofthe Pseudomonas aeruginosa phages <t>KZ, g I44 (J Biol Chem. 2008 Mar 14;283(11):7242-50. Structure of the bacteriophage phi KZ lytic transglycosylase gpl44. Fokine A, Miroshnikov KA, Shneider MM, Mesyanzhinov VV, Rossmann MG.), and EL, El. 1 88 (Mol Microbiol. 2007 Sep;65(5 ): 1334-44. Mura lytic activity and modular structure of the endolysins of Pseudomonas aeruginosa bacteriophages phiKZ and EL. Briers Yl, Volckaert G, Cornelissen A, Lagaert S, Michiels CW, Hertveldt K, Lavigne R), of the phage LUZ24 (NCBI Reference Sequence: YP 001671940.1) as well as of the E. coli phage N4gp61 (J Mol Biol. 2007 Feb 16;366(2):406-19. Coliphage N4 N- acetylmuramidase defines a new family of murein hydrolases. Stojkovic EA1 , Rothman- Denes LB), STM0016 endolysin (NCBI Reference Sequence: NP 459021 .1), PSP3 endolysin (NP 958065.1) and endolysin of Salmonella enteritis phage PVPSE1 (PVP-SEIgpl46 (YP 004893953.1)); Listeria phage endolysins PlyA118 (NCBI Reference Sequence: YP 008666952.1), PlyA500 (NCBI Reference Sequence: YP 001468411.1), PlyPSA (GenBank: CAC85577.1 and J Mol Biol. 2006 Dec 8;364(4):678-89. The crystal structure of the bacteriophage PSA endolysin reveals a unique fold responsible for specific recognition of Listeria cell walls. Korndorfer IP1 , Danzer J, Schmelcher M, Zimmer M, Skerra A, Loessner MJ), PlyA511 (NCBI Reference Sequence: YP 001468459.1), PlyP35 (GenBank: AAY53213.1), PlyP40 (NCBI Reference Sequence: YP 002261442.1), Staphylococcal phage Phi 11 endolysin (Lytic activity of recombinant bacteriophage phi 11 and phi 12 endolysins on whole cells and bio films of Staphylococcus aureus. Sass P, Bierbaum G. Appl Environ Microbiol. 2007 Jan;73(l):347-52), Phi MRU endolysin (NCBI Reference Sequence: YP 001604156.1), LysK (The recombinant phage lysin LysK has a broad spectrum of lytic activity against clinically relevant staphylococci, including methicillin-resistant Staphylococcus aureus. O'Flaherty S, Coffey A, Meaney W, Fitzgerald GF, Ross RP.J Bacteriol. 2005 Oct;187(20):7161-4), Clostridium perfringens PlyS9 (W02010003943 (Al; Bacteriophage. 2012 Apr l;2(2):89-97. Inducible Clostridium perfringens bacteriophages OS9 and OS63: Different genome structures and a fully functional sigK intervening element. Kim KP1 , Born Y, Lurz R, Eichenseher F, Zimmer M, Loessner MJ, Klumpp J.), Ply3626 (Zimmer, M., Scherer, S. and Loessner, M. J. Genomic analysis of Clostridium perfringens bacteriophage phi3626, which integrates into guaA and possibly affects sporulation J. Bacteriol. 184 (16), 4359-4368 (2002)), Clostridium difficile-. CD27L endolysin (J Bacteriol. 2008 0ct;190(20):6734-40. Molecular characterization of a Clostridium difficile bacteriophage and its cloned biologically active endolysin. Mayer MJ1 , Narbad A, Gasson MJ), Streptococcus: B30 endolysin (The bifunctional peptidoglycan lysin of Streptococcus agalactiae bacteriophage B30. Pritchard DG, Dong S, Baker JR, Engler JA. Microbiology. 2004 Jul;150(Pt 7):2079-87), phage Dp-1 encoded Pal amidase (J Biol Chem. 2004 Oct 15;279(42):43697-707. Structural and thermodynamic characterization of Pal, a phage natural chimeric lysin active against pneumococci. Varea JI, Monterroso B, Saiz JL, Lopez-Zumel C, Garcia JL, Laynez J, Garcia P, Menendez M.), Cl endolysin PlyC (PlyC: a multimeric bacteriophage lysin. Nelson D, Schuch R, Chahales P, Zhu S, Fischetti VA. Proc Natl Acad Sci U S A. 2006 Jul 11 ;103(28): 10765-70), Cpl-1 endolysin (Gene. 1990 Jan 31 ;86(1):81-8. Modular organization of the lytic enzymes of Streptococcus pneumoniae and its bacteriophages. Garcia PI, Garcia JL, Garcia E, Sanchez-Puelles JM, Lopez R.), PlyGBS (Antimicrob Agents Chemother. 2005 Jan;49(l): 1 11-7. Removal of group B streptococci colonizing the vagina and oropharynx of mice with a bacteriophage lytic enzyme. Cheng QI, Nelson D, Zhu S, Fischetti VA.), Enterococccus: PlyV12 (J Bacteriol. 2004 Jul;186(14):4808- 12. Identification of a broadly active phage lytic enzyme with lethal activity against antibiotic-resistant Enterococcus faecalis and Enterococcus faecium. Yoong PI, Schuch R, Nelson D, Fischetti VA.). Many antibacterial enzymes are comprised of different domains, such as a cell wall-binding domain and one or more lytic domains exhibiting peptidoglycan hydrolase activity, such as an amidase domain, a peptidase_M23 domain and a CHAP (cysteine, histidine-dependent amidohydrolases/peptidases) domain. Such domains can be used for the design of chimeric endolysins that do not occur in nature. Such endolysins all are explicitly within the scope of the antibacterial enzymes of the embodiments herein.

In the embodiments herein, the chimeric endolysin may be a chimeric endolysin comprising or consisting of a polypeptide having at least about 70% sequence identity or at least 70% sequence identity with an endolysin as set forth in WO2012/150858, W02013/169104, WO2016/142445, WO2017/046021 , WO2015155244, W02015005787, WO2011/023702, WO2012/146738,

W02003/082184, WO2010/011960, WO2010/149795, WO2010/149792, WO2012/094004,

W02011/023702, WO2011/065854, WO2011/076432, WO2011/134998, WO2012/059545,

WO2012/085259, WO2012146738, WO2018/091707..

A preferred bacteriophage endolysin or bacterial lysin is one that has at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with the sequence of a bacteriophage endolysin or bacterial lysin as set forth in SEQ ID NO: 1

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The person skilled in the art will comprehend that individual domains of endolysins disclosed and/or referenced herein may be combined with other domains to result in a chimeric endolysin. Such chimeric endolysins are explicitly within the scope of the antibacterial enzymes of the embodiments herein, such as but not limited to the domains as represented by one of the following sequences: SEQ ID NO:s 82 to 95, or a functional part thereof.

In the embodiments herein, the endolysin or chimeric endolysin may comprise or consist of a polypeptide, or a functional part thereof, having at least about 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80,

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 1.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 2.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 3. In the embodiments herein, the endolysin or chimeric endolysin may comprise or consist of a polypeptide, or a functional part thereof, having at least about 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80,

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 4.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 5.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 6.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 7.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 8.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 9.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 10.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 11.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 12.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 13.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 14.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 15.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 16.

In the embodiments herein, the endolysin or chimeric endolysin may comprise or consist of a polypeptide, or a functional part thereof, having at least about 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 17.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 18.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 19.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NQ:20.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 21.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 22.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 23. In the embodiments herein, the endolysin or chimeric endolysin may comprise or consist of a polypeptide, or a functional part thereof, having at least about 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80,

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 24.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 25.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 26.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 27.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 28.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 29.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 30.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 31.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 32.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 33.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 34.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 35.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 36.

In the embodiments herein, the endolysin or chimeric endolysin may comprise or consist of a polypeptide, or a functional part thereof, having at least about 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 37.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 38.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 39.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 40.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 41.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 42.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 43. In the embodiments herein, the endolysin or chimeric endolysin may comprise or consist of a polypeptide, or a functional part thereof, having at least about 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80,

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 44.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 45.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 46.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 47.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 48.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 49.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 50.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 51.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 52.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 53.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 54.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 55.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 56.

In the embodiments herein, the endolysin or chimeric endolysin may comprise or consist of a polypeptide, or a functional part thereof, having at least about 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 57.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 58.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 59.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 60.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 61.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 62.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 63. In the embodiments herein, the endolysin or chimeric endolysin may comprise or consist of a polypeptide, or a functional part thereof, having at least about 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80,

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 64.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 65.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 66.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 67.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 68.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 69.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 70.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 71.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 72.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 73.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 74.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 75.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 76.

In the embodiments herein, the endolysin or chimeric endolysin may comprise or consist of a polypeptide, or a functional part thereof, having at least about 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 77.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 78.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 79.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 80.

81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 81.

In the embodiments herein, a more preferred compound is a chimeric endolysin comprising or consisting of a polypeptide, or a functional part thereof, having at least about 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity or at least 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99 or 100% sequence identity with an endolysin, or a functional part thereof, as represented by SEQ ID NO: 75.

In the embodiments herein, the antibacterial enzyme may or may not have a tag attached to it, such as a peptide tag useful to facilitate expression and/or affinity purification of the enzyme, to immobilize the enzyme to a surface or to serve as a marker or a label moiety for detection of the enzyme e.g., by antibody binding in different ELISA assay formats. Such tag may be a His-tag, such a C-terminal 6x His-Tag. The person skilled in the art knows how to incorporate a His-tag into an mRNA encoding an antibacterial enzyme. In the embodiments herein, the antibacterial enzyme may or may not have an antibacterial peptide attached to it, such as a cationic or polycationic peptide, an amphipathic peptide, a sushi peptide, a defensin and a hydrophobic peptide. Examples of these antibacterial peptides are the ones set forth in WO2015/155244 and WO2016/142445.

In the embodiments herein, the domains of an antibacterial enzyme, may or may not be separated by a linker. Such linker may be a linker native to the domain or may be a linker foreign to the domain.

The person skilled in the art will comprehend that polypeptides may lack one or more encoded amino acids, especially at the C-terminus or N-terminus of the polypeptide. Accordingly, in the embodiments herein, the antibacterial enzyme may lack one or more amino acids at the C-terminus or N-terminus, such as the M-terminal methionine.

In the embodiments herein, the compound is targeting a bacterial cell for use in the reduction of trans epidermal water loss (TEWL) from a subject by administration of the compound to the subject. In the embodiments herein, the bacterial cell may be any bacterial cell, and is preferably a gram-positive bacterial cell, more preferably a Staphylococcus, even more preferably a Staphylococcus aureus or a Staphylococcus epidermidis.

In the embodiments herein, the TWEL may be caused by any reason. In the embodiments herein, the TWEL may be caused by damage to the skin. The damage to the skin may be caused by any reason. The damage to the skin may be caused by a trauma, such as an injury caused by e.g. an accident and/or a burn. The damage to the skin may be caused by aging, sun burn or by a medical condition such as atopic dermatitis.

In the embodiments herein, the subject may have a specific microbiome of the skin. In the embodiments herein, a Staphylococcus, preferably Staphylococcus aureus may present on and/or in the skin of the subject. In the embodiments herein, a Staphylococcus, preferably Staphylococcus aureus may not present on and/or in the skin of the subject. In the embodiments herein, the skin of the subject may be infected or colonized with a Staphylococcus, preferably Staphylococcus aureus. In the embodiments herein, the skin of the subject may not be infected or colonized with a Staphylococcus, preferably Staphylococcus aureus. Preferably, in the embodiments herein, on the skin of the subject there is substantially no Staphylococcus aureus present but Staphylococcus epidermidis is preferably present. In the embodiments herein, “substantially no Staphylococcus aureus present” means that the viable cell count of Staphylococcus aureus in view of the total viable cell count of the skin microbiome is at most 1 %, preferably at most 0.1 %, even more preferably 0.01 %, and most preferably zero.

In the embodiments herein, the skin of the subject may have lesions. In the embodiments herein, the skin of the subject may not have lesions. In the embodiments herein, the skin of the subject may be infected or colonized with Staphylococcus aureus and the skin may have lesions. In the embodiments herein, the skin of the subject may not be infected or colonized with Staphylococcus aureus and the skin may have lesions. In the embodiments herein, the subject may be a mammal, preferably the subject is a human.

In the embodiments herein, the composition may be any composition known to the person skilled in the art. In the embodiments herein, the composition may be a composition for topical administration.

In the embodiments herein, the composition may further comprise any pharmaceutical or cosmetic excipient or carrier known to the person skilled in the art. Such a pharmaceutically acceptable excipient or herein interchangeably depicted as pharmaceutically acceptable carrier, may be any such carrier or excipient known to the person skilled in the art. Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include, but are not limited to, inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Such excipients may optionally be included in pharmaceutical formulations. Excipients such as cocoa butter and suppository waxes, colouring agents, coating agents, sweetening, flavouring, and/or performing agents can be present in the composition, according to the judgment of the formulator,

Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulphate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and/or combinations thereof.

Exemplar/ granulating and/or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminium silicate, sodium lauryl sulphate, quaternary ammonium compounds, etc., and/or combinations thereof,

Exemplary surface active agents and/or emulsifiers include, but are not limited to, natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatine, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays {e.g. bentonite [aluminium silicate] and magnesium aluminium silicate]), long chain amino acid derivatives, high molecular weight alcohols {e.g. stearyl alcohol, cetyl alcohol, oieyl alcohol, triacetin monostearate, ethylene glycol di-stearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), ear homers {e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan, polyoxyethylene sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, glyceryl monooleate, sorbitan monooleate, polyoxyethylene esters (e.g. polyoxyethylene monostearate, polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, sucrose fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether), polyfvinyl-pyrrolidone), diethylene glycol monolaurate, triethanolaniine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulphate, Poloxamer*188, cetrimonium bromide, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.

Exemplar/ binding agents include, but are not limited to, starch (e.g. cornstarch and starch paste); gelatine; sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol,); natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, micro crystalline cellulose, cellulose acetate, poly(vmyl- pyrrolidone), magnesium aluminium silicate, and larch arabogalactan); alginates; polyethylene oxide; polyethylene glycol; inorganic calcium salts: silicic acid; poiyniethaerylates; waxes; water; alcohol; etc.; and combinations thereof.

Exemplary preservatives may include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and/or other preservatives. Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxy toluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulphite, sodium metabisulphite, and/or sodium sulphite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and/or trisodium edetate. Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, henzethonium chloride, benzyl alcohol bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl, alcohol, glycerine, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenyimercuric nitrate, propylene glycol, and/or thimerosal.

Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and/or sorbic acid. Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and/or phenylethyl alcohol. Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and/or phytic acid. Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulphate (SLS), sodium lauryl ether sulphate (SLES), sodium bisulphite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, methyl paraben.

Exemplary buffering agents include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentadienoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminium hydroxide, alginic acid, pyrogen- free water, isotonic saline, Ringer's solution, ethyl alcohol, etc., and/or combinations thereof.

Exemplary lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulphate, sodium lauryl sulphate, etc., and combinations thereof.

Exemplary oils include, but are not limited to, almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macadamia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughie, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, Shaquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, Tsubaki, vetiver, walnut, and wheat germ oils. Exemplar oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and/or combinations thereof. Preferred excipient are selected from glycerol, propylene glycol, cetearyl alcohol and paraffin.

In the embodiments herein, the composition may be a cosmetic composition or is a pharmaceutical composition.

In the embodiments herein, the compound or composition may be administered as frequently as desired, such as at least once a week, preferably three times a week, preferably once a day, preferably twice a day (bidaily, BID).

In the embodiments herein, the compound or composition may be administered in an amount of endolysin per administration that is at least 5ug/cm² skin, such as at least 6ug/cm² skin, 7ug/cm² skin, 8ug/cm² skin, 9ug/cm² skin, 10ug/cm² skin, 20ug/cm² skin, 30ug/cm² skin, 40ug/cm² skin, 50ug/cm² skin, 60ug/cm² skin, 70ug/cm² skin, 80ug/cm² skin, 90ug/cm² skin, 100ug/cm² skin, 200ug/cm² skin, 300ug/cm² skin, 400ug/cm² skin, or at least 500ug/cm² skin.

In the embodiments herein, the TEWL is preferably reduced significantly, such as by at least 10%, such as by at least 11 , 12, 13, 14, 15, 16, 17, 18, 19 or preferably at least 20%, such as by at least 21 , 22, 23, 24, 25, 26, 27, 28 , 29, or by at least 30%, such as 35%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, at by least 1 log. Preferably, TWEWL is reduced to physiological levels, i.e. to a level of TEWL that would occur without any damage to the skin.

Table 1 : Overview of sequences P62015353WO

Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in WO 2021/213898 Chimeric endolysin in EP22216559.9 Chimeric endolysin in PCT/EP2023/055392 Chimeric endolysin in PCT/EP2023/055392 Chimeric endolysin in PCT/EP2023/055392 Chimeric endolysin in PCT/EP2023/055392 Chimeric endolysin in PCT/EP2023/055393 Chimeric endolysin in PCT/EP2023/055393

Brief description of the Figures:

Figure 1 depicts TEWL from lesional skin (L) and non-lesional skin (NL), assessed at day 15 of treatment, in S. aureus-negative subjects when treated with Gladskin or with a placebo.

Figure 2 depicts TEWL from lesional skin (L) and non-lesional skin (NL), assessed at day 15 of treatment, in S. aureus-negative subjects and S. aureus- positive subjects when treated with Gladskin or with a placebo.

Definitions

"Sequence identity" is herein defined as a relationship between two or more amino acid (peptide, polypeptide, or protein) sequences or two or more nucleic acid (nucleotide, polynucleotide) sequences, as determined by comparing the sequences. In the art, "identity" also means the degree of sequence relatedness between amino acid or nucleotide sequences, as the case may be, as determined by the match between strings of such sequences. "Similarity" between two amino acid sequences is determined by comparing the amino acid sequence and its conserved amino acid substitutes of one peptide or polypeptide to the sequence of a second peptide or polypeptide. In a preferred embodiment, identity or similarity is calculated over the whole SEQ ID NO as identified herein. "Identity" and "similarity" can be readily calculated by known methods, including but not limited to those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W, ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heine, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991 ; and Carillo, H., and Lipman, D., SIAM J. Applied Math., 48:1073 (1988).

Preferred methods to determine identity are designed to give the largest match between the sequences tested. Methods to determine identity and similarity are codified in publicly available computer programs. Preferred computer program methods to determine identity and similarity between two sequences include e.g. the GCG program package (Devereux, J., et al., NucleicAcids Research 12 (1): 387 (1984)), BestFit, BLASTP, BLASTN, and FASTA (Altschul, S. F. et al., J. Mol. Biol. 215:403-410 (1990). The BLAST X program is publicly available from NCBI and other sources (BLAST Manual, Altschul, S., et al., NCBI NLM NIH Bethesda, MD 20894; Altschul, S., et al., J. Mol. Biol. 215:403-410 (1990). The well-known Smith Waterman algorithm may also be used to determine identity.

Preferred parameters for polypeptide sequence comparison include the following: Algorithm: Needleman and Wunsch, J. Mol. Biol. 48:443-453 (1970); Comparison matrix: BLOSUM62 from Hentikoff and Hentikoff, Proc. Natl. Acad. Sci. USA. 89:10915-10919 (1992); Gap Penalty: 12; and Gap Length Penalty: 4. A program useful with these parameters is publicly available as the "Ogap" program from Genetics Computer Group, located in Madison, Wl. The aforementioned parameters are the default parameters for amino acid comparisons (along with no penalty for end gaps).

Preferred parameters for nucleic acid comparison include the following: Algorithm: Needleman and Wunsch, J. Mol. Biol. 48:443-453 (1970); Comparison matrix: matches=+10, mismatch=0; Gap Penalty: 50; Gap Length Penalty: 3. Available as the Gap program from Genetics Computer Group, located in Madison, Wis. Given above are the default parameters for nucleic acid comparisons.

Optionally, in determining the degree of amino acid similarity, the skilled person may also take into account so-called "conservative" amino acid substitutions, as will be clear to the skilled person. Conservative amino acid substitutions refer to the interchangeability of residues having similar side chains. For example, a group of amino acids having aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; a group of amino acids having aliphatic-hydroxyl side chains is serine and threonine; a group of amino acids having amide-containing side chains is asparagine and glutamine; a group of amino acids having aromatic side chains is phenylalanine, tyrosine, and tryptophan; a group of amino acids having basic side chains is lysine, arginine, and histidine; and a group of amino acids having sulphur-containing side chains is cysteine and methionine. Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alaninevaline, and asparagine-glutamine. Substitutional variants of the amino acid sequence disclosed herein are those in which at least one residue in the disclosed sequences has been removed and a different residue inserted in its place. Preferably, the amino acid change is conservative. Preferred conservative substitutions for each of the naturally occurring amino acids are as follows: Ala to ser; Arg to lys; Asn to gin or his; Asp to glu; Cys to ser or ala; Gin to asn; Glu to asp; Gly to pro; His to asn or gin; He to leu or val; Leu to ile or val; Lys to arg; gin or glu; Met to leu or ile; Phe to met, leu or tyr; Ser to thr; Thr to ser; Trp to tyr; Tyr to trp or phe; and, Val to ile or leu.

A “nucleic acid molecule” or “polynucleotide” (the terms are used interchangeably herein) is represented by a nucleotide sequence. A “polypeptide” is represented by an amino acid sequence. A “nucleic acid construct” is defined as a nucleic acid molecule which is isolated from a naturally occurring gene or which has been modified to contain segments of nucleic acids which are combined or juxtaposed in a manner which would not otherwise exist in nature. A nucleic acid molecule is represented by a nucleotide sequence. Optionally, a nucleotide sequence present in a nucleic acid construct is operably linked to one or more control sequences, which direct the production or expression of the peptide or polypeptide in a cell or in a subject.

“Operably linked” is defined herein as a configuration in which a control sequence is appropriately placed at a position relative to the nucleotide sequence coding for the polypeptide of the invention such that the control sequence directs the production/expression of the peptide or polypeptide of the invention in a cell and/or in a subject. “Operably linked” may also be used for defining a configuration in which a sequence is appropriately placed at a position relative to another sequence coding for a functional domain such that a chimeric polypeptide is encoded in a cell and/or in a subject.

“Expression” is construed as to include any step involved in the production of the peptide or polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post- translational modification and secretion.

A “control sequence” is defined herein to include all components which are necessary or advantageous for the expression of a polypeptide. At a minimum, the control sequences include a promoter and transcriptional and translational stop signals. Optionally, a promoter represented by a nucleotide sequence present in a nucleic acid construct is operably linked to another nucleotide sequence encoding a peptide or polypeptide as identified herein.

The term "transformation" refers to a permanent or transient genetic change induced in a cell following the incorporation of new DNA (i.e. DNA exogenous to the cell). When the cell is a bacterial cell, as is intended in the present invention, the term usually refers to an extrachromosomal, self-replicating vector which harbors a selectable antibiotic resistance.

An “expression vector” may be any vector which can be conveniently subjected to recombinant DNA procedures and can bring about the expression of a nucleotide sequence encoding a polypeptide of the invention in a cell and/or in a subject. As used herein, the term "promoter" refers to a nucleic acid fragment that functions to control the transcription of one or more genes or nucleic acids, located upstream with respect to the direction of transcription of the transcription initiation site of the gene. It is related to the binding site identified by the presence of a binding site for DNA-dependent RNA polymerase, transcription initiation sites, and any other DNA sequences, including, but not limited to, transcription factor binding sites, repressor and activator protein binding sites, and any other sequences of nucleotides known to one skilled in the art to act directly or indirectly to regulate the amount of transcription from the promoter. Within the context of the invention, a promoter preferably ends at nucleotide -1 of the transcription start site (TSS).

A “polypeptide” or “protein" as used herein refers to any peptide, oligopeptide, polypeptide, gene product, expression product, or protein. A polypeptide is comprised of consecutive amino acids. The term "polypeptide" encompasses naturally occurring or synthetic molecules.

The term “recombinant polypeptide” or “recombinant protein” as used herein refers to a polypeptide that is produced in a cell of a different species or type as compared to the species or type of cell that produces the polypeptide in nature, or that is produced in a cell at a level at which it is not produced in nature.

The term "heterogeneous" as used herein with reference to a plurality of recombinant proteins means that the plurality of recombinant proteins comprises at least two or two or more, three or more, four or more, five or more, six or more, or seven or more proteins of differing amino acid sequence.

The term "mature" as used herein with reference to a protein refers to the protein, or amino acid sequence of the protein, after cleavage of the signal sequence. The term "full length" as used herein with reference to a protein refers to the protein, or amino acid sequence of the protein, comprising the signal sequence. Examples of mature and full-length proteins are provided in Table 1 herein.

The term "wild-type" as used herein with reference to proteins or polynucleotides refers to a protein or polynucleotide having an amino acid or nucleotide sequences that is the same as that expressed naturally. This term includes all naturally occurring variants of a particular protein, for example, all naturally occurring variants of p-lactoglobulin. Furthermore, this term includes both full length proteins and mature proteins and polynucleotides that encode wild-type full length and mature protein. The term is generally synonymous with the term "native".

Sequence identity of any polynucleotide, any polynucleotide construct or any polypeptide herein is preferably at least 70%. Preferably at least 70% is defined as preferably at least 70%, more preferably at least 71 %, more preferably at least 72%, more preferably at least 73%, more preferably at least 74%, more preferably at least 75%, more preferably at least 76%, more preferably at least 77%, more preferably at least 78%, more preferably at least 79%, more preferably at least 80%, more preferably at least 81 %, more preferably at least 82%, more preferably at least 83%, more preferably at least 84%, more preferably at least 85%, more preferably at least 86%, more preferably at least 87%, more preferably at least 88%, more preferably at least 89%, more preferably at least 90%, more preferably at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, more preferably at least 98%, more preferably at least 99%, or most preferably 100% sequence identity. In case of 100% sequence identity, the polynucleotide or polypeptide has exactly the sequence of the depicted SEQ ID NO:. Sequence identity of any polynucleotide, any polynucleotide construct or any polypeptide herein is preferably determined over the entire length of the subject sequence. The sequence information as provided herein should not be so narrowly construed as to require inclusion of erroneously identified bases. The skilled person is capable of identifying such erroneously identified bases and knows how to correct for such errors.

In this document and in its claims, the verbs "to comprise", “to contain”, and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. In addition, the verb “to consist of’ may be replaced by “to consist essentially of’ meaning that a product or a composition or a nucleic acid molecule or a peptide or polypeptide of a nucleic acid construct or vector or cell as defined herein may comprise additional component(s) than the ones specifically identified; the additional component(s) not altering the unique characteristic of the invention. In addition, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there be one and only one of the elements. The indefinite article "a" or "an" thus usually means "at least one". The word “about” or “approximately” when used in association with a numerical value (e.g. about 10) preferably means that the value may be the given value (of 10) more or less 10% of the value.

All patent and literature references cited in the present specification are hereby incorporated by reference in their entirety.

Unless otherwise indicated each embodiment as described herein may be combined with another embodiment as described herein.

Unless stated otherwise, reference to such sources of information is not to be construed, in any jurisdiction, as an admission that such sources of information are prior art or form part of the common general knowledge in the art.

Further embodiments

Further embodiments of the invention are listed here below.

1 . A compound targeting a bacterial cell for use in the reduction of trans epidermal water loss (TEWL) from a subject by administration of the compound to the subject.

2. A composition comprising a compound targeting a bacterial cell for use in the reduction of TEWL from a subject by administration of the composition to the subject.

3. The compound for use or the composition for use according to embodiment 1 or 2, wherein the compound comprises at least one cell wall binding domain specifically binding the peptidoglycan cell wall of said bacterial cell.

4. The compound for use or the composition for use according to embodiment 3, wherein the cell wall binding domain originates from or is a homologue of a cell wall binding domain of a bacteriophage endolysin or of a bacterial lysin.

5. The compound for use or the composition for use according to any one of embodiments 1 to 4, wherein the compound comprises one or more enzymatic active domains exhibiting specificity for an essential bond in the peptidoglycan layer of said bacterial cell. 6. The compound for use or the composition for use according to embodiment 5, wherein the enzymatic active domain is a cysteine, histidine dependent amidohydrolase/peptidase (CHAP) domain, an endopeptidase domain, an amidase domain or a glycosylhydrolase domain.

7. The compound for use or the composition for use according to embodiment 5 or 6, wherein the enzymatic active domain originates from or is a homologue of a cell wall binding domain of a bacteriophage endolysin or of a bacterial lysin.

8. The compound for use or the composition for use according to any one of embodiments 1 to 7, wherein the bacterial cell is a gram-positive bacterial cell, preferably a Staphylococcus, more preferably a Staphylococcus aureus or a Staphylococcus epidermidis.

9. The compound for use or composition for use according to any one of embodiments 1 to 8, wherein the TEWL is caused by damage to the skin.

10. The compound for use or composition for use according to embodiment 9, wherein the damage to the skin is caused by a trauma, such as an injury caused by e.g. an accident and/or a burn.

11 . The compound for use or composition for use according to embodiment 9, wherein the damage to the skin is caused by aging, sun burn or by a medical condition such as atopic dermatitis.

12. The compound for use or composition for use according to any one of embodiments 1 to 11 , wherein Staphylococcus aureus is present on and/or in the skin of the subject.

13. The compound for use or composition for use according to any one of embodiments 1 to 11 , wherein Staphylococcus aureus is not present on and/or in the skin of the subject.

14. The compound for use or composition for use according to any one of embodiments 1 to 11 , wherein the skin of the subject is infected or colonized with a Staphylococcus, preferably Staphylococcus aureus.

15. The compound for use or composition for use according to any one of embodiments 1 to 11 , wherein the skin of the subject is not infected or colonized with a Staphylococcus, preferably Staphylococcus aureus.

16. The compound for use or composition for use according to any one of embodiments 1 to 11 , wherein on the skin of the subject there is substantially no Staphylococcus aureus present but Staphylococcus epidermidis is present.

17. The compound for use or composition for use according to any one of embodiments 1 to 16, wherein the skin of the subject has lesions.

18. The compound for use or composition for use according to any one of embodiments 1 to 16, wherein the skin of the subject has no lesions.

19. The compound for use or composition for use according to any one of embodiments 1 to 11 , wherein the skin of the subject is infected or colonized with Staphylococcus aureus and the skin has lesions.

20. The compound for use or composition for use according to any one of embodiments 1 to 11 , wherein the skin of the subject is not infected or colonized with Staphylococcus aureus and the skin has lesions.

21 . The compound for use or composition for use according to any one of embodiments 1 to 20, wherein the subject is a mammal, preferably a human. 22. The composition for use according to any one of embodiments 2 to 21 , wherein the composition is a composition for topical administration.

23. The composition for use according to any one of embodiments 2 to 22, wherein the composition further comprises a pharmaceutical or a cosmetic excipient, preferably selected from glycerol, propylene glycol, cetearyl alcohol, and paraffin.

24. The composition for use according to any one of embodiments 2 to 23, wherein the composition is a cosmetic composition or is a pharmaceutical composition.

25. The compound for use or composition for use according to any one of embodiments 1 to 24, wherein administration is as frequently as desired, such as at least once a week, preferably three times a week, preferably once a day, preferably twice a day (BID).

26. The compound for use or composition for use according to any one of embodiments 1 to 25, wherein the amount of endolysin per administration is at least 10ug/cm² skin.

27. The compound for use or composition for use according to any one of embodiments 1 to 26, wherein the TEWL is reduced by at least 10%, preferably at least 15%.

28. Use of compound targeting a bacterial cell in the reduction of trans epidermal water loss (TEWL) from a subject by administration of the compound to the subject.

29. Use of composition comprising a compound targeting a bacterial cell in the reduction of TEWL from a subject by administration of the composition to the subject.

30. The use according to embodiment 28 or 29, wherein the compound comprises at least one cell wall binding domain specifically binding the peptidoglycan cell wall of said bacterial cell.

31 . The use according to embodiment 30, wherein the cell wall binding domain originates from or is a homologue of a cell wall binding domain of a bacteriophage endolysin or of a bacterial lysin.

32. The use according to any one of embodiments 28 to 31 , wherein the compound comprises one or more enzymatic active domains exhibiting specificity for an essential bond in the peptidoglycan layer of said bacterial cell.

33. The use according to embodiment 32, wherein the enzymatic active domain is a cysteine, histidine dependent amidohydrolase/peptidase (CHAP) domain, an endopeptidase domain, an amidase domain or a glycosylhydrolase domain.

34. The use according to embodiment 32 or 33, wherein the enzymatic active domain originates from or is a homologue of a cell wall binding domain of a bacteriophage endolysin or of a bacterial lysin.

35. The use according to embodiments 29 to 34, wherein the bacterial cell is a gram-positive bacterial cell, preferably a Staphylococcus, more preferably a Staphylococcus aureus or a Staphylococcus epidermidis.

36. The use according to embodiments 29 to35, wherein the TEWL is caused by damage to the skin.

37. The use according to embodiment 36, wherein the damage to the skin is caused by a trauma, such as an injury caused by e.g. an accident and/or a burn.

38. The use according to embodiment 37, wherein the damage to the skin is caused by aging, sun burn or by a medical condition such as atopic dermatitis.

39. The use according to any one of embodiments 28 to 38, wherein Staphylococcus aureus is present on and/or in the skin of the subject. 40. The use according to any one of embodiments 28 to 38, wherein Staphylococcus aureus is not present on and/or in the skin of the subject.

41 . The use according to any one of embodiments 28 to 38, wherein the skin of the subject is infected or colonized with a Staphylococcus, preferably Staphylococcus aureus.

42. The use according to any one of embodiments 28 to 38, wherein the skin of the subject is not infected or colonized with a Staphylococcus, preferably Staphylococcus aureus.

43. The use according to any one of embodiments 28 to 38, wherein on the skin of the subject there is substantially no Staphylococcus aureus present but Staphylococcus epidermidis is present.

44. The use or composition for use according to any one of embodiments 28 to 43, wherein the skin of the subject has lesions.

45. The use or composition for use according to any one of embodiments 28 to 43, wherein the skin of the subject has no lesions.

46. The use or composition for use according to any one of embodiments 28 to 38, wherein the skin of the subject is infected or colonized with Staphylococcus aureus and the skin has lesions.

47. The use or composition for use according to any one of embodiments 28 to 38, wherein the skin of the subject is not infected or colonized with Staphylococcus aureus and the skin has lesions.

48. The use according to any one of embodiments 28 to 47, wherein the subject is a mammal, preferably a human.

49. The use according to any one of embodiments 29 to 48, wherein the composition is a composition for topical administration.

50. The use according to any one of embodiments 29 to 49, wherein the composition further comprises a pharmaceutical or a cosmetic excipient, preferably selected from glycerol, propylene glycol, cetearyl alcohol, and paraffin.

51 . The use according to any one of embodiments 29 to 50, wherein the composition is a cosmetic composition or is a pharmaceutical composition.

52. The use according to any one of embodiments 28 to 51 , wherein administration is as frequently as desired, such as at least once a week, preferably three times a week, preferably once a day, preferably twice a day (BID).

53. The use according to any one of embodiments 28 to 52, wherein the amount of endolysin per administration is at least 10ug/cm² skin.

54. The use according to any one of embodiments 28 to 53, wherein the TEWL is reduced by at least 10%, preferably at least 15%.

55. A method for the reduction of trans epidermal water loss (TEWL) from a subject by administration of a compound targeting a bacterial cell to the subject.

56. A method for the reduction of TEWL from a subject by administration of a composition comprising a compound targeting a bacterial cell to the subject.

57. The method according to embodiment 55 or 56, wherein the compound comprises at least one cell wall binding domain specifically binding the peptidoglycan cell wall of said bacterial cell.

58. The method according to embodiment 57, wherein the cell wall binding domain originates from or is a homologue of a cell wall binding domain of a bacteriophage endolysin or of a bacterial lysin. 59. The method according to any one of embodiments 55 to 58, wherein the compound comprises one or more enzymatic active domains exhibiting specificity for an essential bond in the peptidoglycan layer of said bacterial cell.

60. The method according to embodiment 59, wherein the enzymatic active domain is a cysteine, histidine dependent amidohydrolase/peptidase (CHAP) domain, an endopeptidase domain, an amidase domain or a glycosylhydrolase domain.

61 . The method according to embodiment 59 or 60, wherein the enzymatic active domain originates from or is a homologue of a cell wall binding domain of a bacteriophage endolysin or of a bacterial lysin.

62. The method according to embodiments 55 to 61 , wherein the bacterial cell is a gram-positive bacterial cell, preferably a Staphylococcus, more preferably a Staphylococcus aureus or a Staphylococcus epidermidis.

63. The method according to embodiments 55 to 62, wherein the TEWL is caused by damage to the skin.

64. The method according to embodiment 63, wherein the damage to the skin is caused by a trauma, such as an injury caused by e.g. an accident and/or a burn.

65. The method according to embodiment 63, wherein the damage to the skin is caused by aging, sun burn or by a medical condition such as atopic dermatitis.

66. The method according to any one of embodiments 55 to 65, wherein Staphylococcus aureus is present on and/or in the skin of the subject.

67. The method according to any one of embodiments 55 to 65, wherein Staphylococcus aureus is not present on and/or in the skin of the subject.

68. The method according to any one of embodiments 55 to 65, wherein the skin of the subject is infected or colonized with a Staphylococcus, preferably Staphylococcus aureus.

69. The method according to any one of embodiments 55 to 65, wherein the skin of the subject is not infected or colonized with a Staphylococcus, preferably Staphylococcus aureus.

70. The method according to any one of embodiments 55 to 65, wherein on the skin of the subject there is substantially no Staphylococcus aureus present but Staphylococcus epidermidis is present.

71. The method according to any one of embodiments 55 to 70, wherein the skin of the subject has lesions.

72. The method according to any one of embodiments 55 to 70, wherein the skin of the subject has no lesions.

73. The method according to any one of embodiments 55 to 65, wherein the skin of the subject is infected or colonized with Staphylococcus aureus and the skin has lesions.

74. The method according to any one of embodiments 55 to 65, wherein the skin of the subject is not infected or colonized with Staphylococcus aureus and the skin has lesions.

75. The method according to any one of embodiments 55 to 74, wherein the subject is a mammal, preferably a human. 76. The method according to any one of embodiments 56 to 75, wherein the composition is a composition for topical administration.

77. The method according to any one of embodiments 56 to 76, wherein the composition further comprises a pharmaceutical or a cosmetic excipient, preferably selected from glycerol, propylene glycol, cetearyl alcohol, and paraffin.

78. The method according to any one of embodiments 56 to 77, wherein the composition is a cosmetic composition or is a pharmaceutical composition.

79. The method according to any one of embodiments 55 to 78, wherein administration is as frequently as desired, such as at least once a week, preferably three times a week, preferably once a day, preferably twice a day (BID).

80. The method according to any one of embodiments 55 to 79, wherein the amount of endolysin per administration is at least 10ug/cm² skin.

81 . The method according to any one of embodiments 55 to 80, wherein the TEWL is reduced by at least 10%, preferably at least 15%.

82. A method of treatment to reduce trans epidermal water loss (TEWL) from a subject by administration of a compound targeting a bacterial cell to the subject.

83. A method of treatment to reduce TEWL from a subject by administration of a composition comprising a compound targeting a bacterial cell to the subject.

84. The method of treatment according to embodiment 82 or 83, wherein the compound comprises at least one cell wall binding domain specifically binding the peptidoglycan cell wall of said bacterial cell.

85. The method of treatment according to embodiment 84, wherein the cell wall binding domain originates from or is a homologue of a cell wall binding domain of a bacteriophage endolysin or of a bacterial lysin.

86. The method of treatment according to any one of embodiments 82 to 85, wherein the compound comprises one or more enzymatic active domains exhibiting specificity for an essential bond in the peptidoglycan layer of said bacterial cell.

87. The method of treatment according to embodiment 83, wherein the enzymatic active domain is a cysteine, histidine dependent amidohydrolase/peptidase (CHAP) domain, an endopeptidase domain, an amidase domain or a glycosylhydrolase domain.

88. The method of treatment according to embodiment 86 or 87, wherein the enzymatic active domain originates from or is a homologue of a cell wall binding domain of a bacteriophage endolysin or of a bacterial lysin.

89. The method of treatment according to embodiments 82 to 88, wherein the bacterial cell is a grampositive bacterial cell, preferably a Staphylococcus, more preferably a Staphylococcus aureus or a Staphylococcus epidermidis.

90. The method of treatment according to embodiments 82 to 89, wherein the TEWL is caused by damage to the skin.

91 . The method of treatment according to embodiment 90, wherein the damage to the skin is caused by a trauma, such as an injury caused by e.g. an accident and/or a burn. 92. The method of treatment according to embodiment 90, wherein the damage to the skin is caused by aging, sun burn or by a medical condition such as atopic dermatitis.

93. The method of treatment according to any one of embodiments 82 to 92, wherein Staphylococcus aureus is present on and/or in the skin of the subject.

94. The method of treatment according to any one of embodiments 82 to 93, wherein Staphylococcus aureus is not present on and/or in the skin of the subject.

95. The method of treatment according to any one of embodiments 82 to 93, wherein the skin of the subject is infected or colonized with a Staphylococcus, preferably Staphylococcus aureus.

96. The method of treatment according to any one of embodiments 82 to 93, wherein the skin of the subject is not infected or colonized with a Staphylococcus, preferably Staphylococcus aureus.

97. The method of treatment according to any one of embodiments 82 to 93, wherein on the skin of the subject there is substantially no Staphylococcus aureus present but Staphylococcus epidermidis is present.

98. The method of treatment according to any one of embodiments 82 to 97, wherein the skin of the subject has lesions.

99. The method of treatment according to any one of embodiments 82 to 97, wherein the skin of the subject has no lesions.

100. The method of treatment according to any one of embodiments 82 to 93, wherein the skin of the subject is infected or colonized with Staphylococcus aureus and the skin has lesions.

101. The method of treatment according to any one of embodiments 82 to 93, wherein the skin of the subject is not infected or colonized with Staphylococcus aureus and the skin has lesions.

102. The method of treatment according to any one of embodiments 82 to 01 , wherein the subject is a mammal, preferably a human.

103. The method of treatment according to any one of embodiments 83 to 102, wherein the composition is a composition for topical administration.

104. The method of treatment according to any one of embodiments 83 to 103, wherein the composition further comprises a pharmaceutical or a cosmetic excipient, preferably selected from glycerol, propylene glycol, cetearyl alcohol, and paraffin.

105. The method of treatment according to any one of embodiments 83 to 104, wherein the composition is a cosmetic composition or is a pharmaceutical composition.

106. The method of treatment according to any one of embodiments 82 to 105, wherein administration is as frequently as desired, such as at least once a week, preferably three times a week, preferably once a day, preferably twice a day (BID).

107. The method of treatment according to any one of embodiments 82 to 106, wherein the amount of endolysin per administration is at least 10ug/cm² skin.

108. The method of treatment according to any one of embodiments 82 to 107, wherein the TEWL is reduced by at least 10%, preferably at least 15%.

109. Use of compound targeting a bacterial cell for the manufacture of a medicament for the reduction of trans epidermal water loss (TEWL) from a subject by administration of the compound to the subject. 110. Use of composition comprising a compound targeting a bacterial cell for the manufacture of a medicament for the reduction of TEWL from a subject by administration of the composition to the subject.

111. The use according to embodiment 109 or 110, wherein the compound comprises at least one cell wall binding domain specifically binding the peptidoglycan cell wall of said bacterial cell.

112. The use according to embodiment 111 , wherein the cell wall binding domain originates from or is a homologue of a cell wall binding domain of a bacteriophage endolysin or of a bacterial lysin.

113. The use according to any one of embodiments 109 to 112, wherein the compound comprises one or more enzymatic active domains exhibiting specificity for an essential bond in the peptidoglycan layer of said bacterial cell.

114. The use according to embodiment 113, wherein the enzymatic active domain is a cysteine, histidine dependent amidohydrolase/peptidase (CHAP) domain, an endopeptidase domain, an amidase domain or a glycosylhydrolase domain.

115. The use according to embodiment 113 or 114, wherein the enzymatic active domain originates from or is a homologue of a cell wall binding domain of a bacteriophage endolysin or of a bacterial lysin.

116. The use according to embodiments 109 to 115, wherein the bacterial cell is a gram-positive bacterial cell, preferably a Staphylococcus, more preferably a Staphylococcus aureus or a Staphylococcus epidermidis.

117. The use according to embodiments 109 to 117, wherein the TEWL is caused by damage to the skin.

118. The use according to embodiment 117, wherein the damage to the skin is caused by a trauma, such as an injury caused by e.g. an accident and/or a burn.

119. The use according to embodiment 117, wherein the damage to the skin is caused by aging, sun burn or by a medical condition such as atopic dermatitis.

120. The use according to any one of embodiments 109 to 119, wherein Staphylococcus aureus is present on and/or in the skin of the subject.

121 . The use according to any one of embodiments 109 to 120, wherein Staphylococcus aureus is not present on and/or in the skin of the subject.

122. The use according to any one of embodiments 109 to 121 , wherein the skin of the subject is infected or colonized with a Staphylococcus, preferably Staphylococcus aureus.

123. The use according to any one of embodiments 109 to 121 , wherein the skin of the subject is not infected or colonized with a Staphylococcus, preferably Staphylococcus aureus.

124. The use according to any one of embodiments 109 to 121 , wherein on the skin of the subject there is substantially no Staphylococcus aureus present but Staphylococcus epidermidis is present.

125. The use or composition for use according to any one of embodiments 109 to 124, wherein the skin of the subject has lesions.

126. The use or composition for use according to any one of embodiments 109 to 124, wherein the skin of the subject has no lesions. 127. The use or composition for use according to any one of embodiments 109 to 121 , wherein the skin of the subject is infected or colonized with Staphylococcus aureus and the skin has lesions.

128. The use or composition for use according to any one of embodiments 109 to 121 , wherein the skin of the subject is not infected or colonized with Staphylococcus aureus and the skin has lesions.

129. The use according to any one of embodiments 109 to 128, wherein the subject is a mammal, preferably a human.

130. The use according to any one of embodiments 110 to 129, wherein the composition is a composition for topical administration.

131. The use according to any one of embodiments 110 to 130, wherein the composition further comprises a pharmaceutical or a cosmetic excipient, preferably selected from glycerol, propylene glycol, cetearyl alcohol, and paraffin.

132. The use according to any one of embodiments 110 to 131 , wherein the composition is a cosmetic composition or is a pharmaceutical composition.

133. The use according to any one of embodiments 109 to 132, wherein administration is as frequently as desired, such as at least once a week, preferably three times a week, preferably once a day, preferably twice a day (BID).

134. The use according to any one of embodiments 109 to 133, wherein the amount of endolysin per administration is at least 10ug/cm² skin.

135. The use according to any one of embodiments 109 to 134, wherein the TEWL is reduced by at least 10%, preferably at least 15%.

Examples

The following examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. In this specification, where reference has been made to external sources of information, including patent specifications and other documents, this is generally for the purpose of providing a context for discussing the features of the present invention.

Example 1 ; Reduction of trans epidermal water loss (TEWL) from a subject by administration of a compound targeting abacterial cell to the subject

Introduction

The inventors have established during a clinical trial of antibacterial therapy to treat atopic dermatitis that the administration to a subject of a polypeptide with antibacterial properties surprisingly reduces trans epidermal water loss (TEWL). In the clinical trial an endolysin was used that is effective against Staphylococcus (S.) aureus.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is associated with reduced quality of life, primarily due to itchy skin (Bieber et al, 2008; Lewis-Jones wet al, 2006; Ben-Gashir et al, 2004). The disease is characterised by reduced skin microbial diversity and overgrowth of Staphylococcus (S.) aureus, a bacterium that can aggravate skin inflammation via the production of staphylococcal enterotoxins that stimulate the release of pro-inflammatory cytokines (Totte et al, 2016; Kong et al, 2012; Travers et al, 2014; Biedermann et al, 2015). However, the importance of S. aureus colonisation in the complex pathogenesis, compared to the other genetic and immunologic factors involved, remains unclear.

In the context of the increasing incidence of bacterial resistance, the interest in bacteriophages and their endolysins as antibacterial therapy has been renewed (Knoll et al, 2014). Staphefekt SA.100 is an engineered chimeric endolysin with an amino acid sequence as set forth in SEQ ID NO: 75 that specifically lyses the cell membrane of S. aureus via endopeptidase and amidase activities (Fluit et al, 2012; Herpers et al, 2014; Herpers et al, 2014(2). Long-term application of Staphefekt on the skin, targeting only S. aureus and leaving skin commensals unharmed, improves long-term atopic dermatitis outcomes, such as reduction of the number of disease flares, and allows reduction the use of topical corticosteroids. Bacterial resistance to Staphefekt or other endolysins has not been observed and could not be induced, which enabled to study the effect of long-term anti-staphylococcal treatment in atopic dermatitis subjects that are not infected or colonized with S. aureus using this endolysin-based agent (Fischetti et al, 2016; Pastagia et al, 2013).

The aim of the randomized controlled trial was to evaluate the effect of 3-month anti-staphylococcal therapy with Staphefekt wherein several parameters associated with disease were monitored.

Materials and Methods

The MAAS trial (Microbiome in atopic dermatitis during anti-staphylococcal therapy and the effect on steroid use; ClinicalTrials.gov, NCT02840955. Registered on 11 July 2016), was a multi-centre, randomized, double-blinded, placebo-controlled superiority trial with a parallel group design. The study evaluated the effect of Staphefekt on the use of corticosteroids, disease severity, quality of life and composition of the microbiome in patients with AD. The study was designed by the Department of Dermatology of the Erasmus MC University Medical Centre Rotterdam and was executed in collaboration with the Havenziekenhuis Rotterdam. Enrolment and follow-up visits took place at these two locations. Participants who comply with the criteria for inclusion and exclusion started with a 2-week run-in period to standardize the corticosteroid use with triamcinolone acetonide 0.1 % cream. After completion of the run-in phase, participants were randomized to either treatment with Staphefekt or a placebo for 12 weeks (End of Treatment, EOT), followed by an 8-week follow-up period (End of Study, EOS). Subjects were administered bidaily Gladskin Eczema Cream with Staphefekt (depicted as “Gladskin”) or without Staphefekt (depicted as “Placebo"). Gladskin Eczema Cream contains 35 pg/mL of Staphefekt. During the course of the study, participants visited the outpatient clinic six times (visit 1 through 6) and data was collected on corticosteroid use, disease severity, quality of life, skin microbiome and adverse events.

Results and discussion

Besides that the use of Staphefekt was effective in the treatment of atopic dermatitis, it was surprisingly found that the use of Staphefekt reduced trans epidermal water loss (TEWL) in subjects infected or colonized with S. aureus and in subjects not infected or colonized with S. aureus. The results are depicted in Table 2 here below. Table 3 here below depicts the effect of Gladskin versus placebo on TEWL on the skin of Staphylococcus aureus negative subjects with or without lesions. The data are graphically represented in Figure 1 .

L: Lesions NL: No lesions

Subjects have arbitrary numbers

Table 4 here below depicts the effect of Gladskin versus placebo on TEWL on the skin of Staphylococcus aureus positive and negative subjects with or without lesions. The data are graphically represented in Figure 2.

GS: Gladskin

P: Placebo

L: Lesions

NL: No lesions

Subjects have arbitrary numbers

As can clearly be observed from the data, see e.g. Figures 1 and 2, the use of Staphefekt reduced trans epidermal water loss (TEWL) in subjects infected or colonized with S. aureus and in subjects not infected or colonized with S. aureus. The effect was most pronounced in subjects not infected or colonized with S. aureus. In addition, the effect was more pronounced in subjects having lesions compared to subjects having no lesions.

References:

Green et al., (2022) Skin Health Dis; 2(2):e104. doi: 10.1002/ski2.104.

Gioia et al., (2002) The dynamics of TWL from hydrated skin. Skin Research and Technology Vol. 8 pp. 178-186. Kottner et al., (2013) Transepidermal water loss in young and aged healthy humans: a systematic review and meta-analysis, Arch Dermatol Res Vol. 305 pp. 315-323, doi:10.1007/s00403-012-1313- 6

Gardien et al., (2016) Transepidermal water loss measured with the Tewameter TM300 in burn scars. Burns Vol. 42(7) pp. 1455-1462, doi:10.1016/j.burns.2016.04.018

Underhill, Frank P. (1927) The Significance ofAnhydremia in Extensive Superficial Burns Journal of the American Medical Association Vol. 95 No. 12.

Artz, Lieut. Col. Curtis P. and Capt. Harry S. Soroff (MC) (1955) Modern Concepts in the Treatment of Burns Journal of the American Medical Association Vol. 159 No. 5

Ahuja, Rajeev B. and Sameek Bhattacharya (2004) Burns in the developing world and burn disasters British Medical Journal Vol. 329.

Chilcott, Robert et al. (2002) Transepidermal water loss does not correlate with skin barrier function in vitro The Journal of Investigative Dermatology Vol. 118 pp. 871-875

Bieber T. Atopic dermatitis. N Engl J Med. 2008;358(14):1483-94.

Lewis-Jones S. Quality of life and childhood atopic dermatitis: the misery of living with childhood eczema. Int J Clin Pract. 2006;60(8):984-92.

Ben-Gashir MA, Seed PT, Hay RJ. Quality of life and disease severity are correlated in children with atopic dermatitis. Br J Dermatol. 2004;150(2):284-90.

Totte JE, van der Feltz WT, Hennekam M, van Belkum A, van Zuuren EJ, Pasmans SG. Prevalence and odds of Staphylococcus aureus carriage in atopic dermatitis: a systematic review and meta- analysis. Br J Dermatol. 2016;175(4):687-95.

Kong HH, Oh J, Deming C, Conlan S, Grice EA, Beatson MA, et al. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res. 2012;22(5):850-9.

Travers JB. Toxic interaction between Th2 cytokines and Staphylococcus aureus in atopic dermatitis. J Invest Dermatol. 2014;134(8):2069-71.

Biedermann T, Skabytska Y, Kaesler S, Volz T. Regulation of T cell immunity in atopic dermatitis by microbes: the yin and yang of cutaneous inflammation. Front Immunol. 2015;6:353.

Knoll BM, Mylonakis E. Antibacterial bioagents based on principles of bacteriophage biology: an overview. Clin Infect Dis. 2014;58(4):528-34.

Fluit AC, van Marm S, Eichenseher F, Loessner MJ, Pietersma F, Boel CHE. Killing and lysis of Staphylococcus aureus and other staphylococci by an endolysin. 52th ICAAC, abstract F-1516; San Francisco; 2012.

Herpers BL, Badoux P, Pietersma F, Eichenseher F, Loessner MJ. Specific lysis of methicillin susceptible and resistant Staphylococcus aureus by the endolysin Staphefekt SA.100 TM [abstract]. 24th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID). Barcelona; 2014. Abstract R144.

(2) Herpers BL, Badoux P, Totte JEE, Pietersma F, Eichenseher F, Loessner MJ, editors. Specific lysis of Staphylococcus aureus by the bacteriophage endolysin staphefekt SA.100: in vitro studies and human case series. EuroSciCon meeting; Submission for presentation on 5th November 2014; London; 2014.

Fischetti VA. Lysin therapy for Staphylococcus aureus and other bacterial pathogens. Curr Top Microbiol Immunol. 2016.

Pastagia M, Schuch R, Fischetti VA, Huang DB. Lysins: the arrival of pathogen-directed anti-infectives. J Med Microbiol. 2013;62(Pt 10):1506-16.

Claims

45 P62015353WO CLAIMS

3. The compound for use or the composition for use according to claim 1 or 2, wherein the compound comprises at least one cell wall binding domain specifically binding the peptidoglycan cell wall of said bacterial cell.

4. The compound for use or the composition for use according to claim 3, wherein the cell wall binding domain originates from or is a homologue of a cell wall binding domain of a bacteriophage endolysin or of a bacterial lysin.

5. The compound for use or the composition for use according to any one of claims 1 to 4, wherein the compound comprises one or more enzymatic active domains exhibiting specificity for an essential bond in the peptidoglycan layer of said bacterial cell.

6. The compound for use or the composition for use according to claim 5, wherein the enzymatic active domain is a cysteine, histidine dependent amidohydrolase/peptidase (CHAP) domain, an endopeptidase domain, an amidase domain or a glycosylhydrolase domain.

7. The compound for use or the composition for use according to claim 5 or 6, wherein the enzymatic active domain originates from or is a homologue of a cell wall binding domain of a bacteriophage endolysin or of a bacterial lysin.

8. The compound for use or the composition for use according to any one of claims 1 to 7, wherein the bacterial cell is a gram-positive bacterial cell, preferably a Staphylococcus, more preferably a Staphylococcus aureus or a Staphylococcus epidermidis.

9. The compound for use or composition for use according to any one of claims 1 to 8, wherein the TEWL is caused by damage to the skin.

10. The compound for use or composition for use according to claim 9, wherein the damage to the skin is caused by a trauma, such as an injury caused by e.g. an accident and/or a burn.

11 . The compound for use or composition for use according to claim 9, wherein the damage to the skin is caused by aging, sun burn or by a medical condition such as atopic dermatitis. 46

P62015353WO

12. The compound for use or composition for use according to any one of claims 1 to 11 , wherein Staphylococcus aureus is present on and/or in the skin of the subject.

13. The compound for use or composition for use according to any one of claims 1 to 11 , wherein Staphylococcus aureus is not present on and/or in the skin of the subject.

14. The compound for use or composition for use according to any one of claims 1 to 11 , wherein the skin of the subject is infected or colonized with a Staphylococcus, preferably Staphylococcus aureus.

15. The compound for use or composition for use according to any one of claims 1 to 11 , wherein the skin of the subject is not infected or colonized with a Staphylococcus, preferably Staphylococcus aureus.

16. The compound for use or composition for use according to any one of claims 1 to 11 , wherein on the skin of the subject there is substantially no Staphylococcus aureus present but Staphylococcus epidermidis is present.

17. The compound for use or composition for use according to any one of claims 1 to 16, wherein the skin of the subject has lesions.

18. The compound for use or composition for use according to any one of claims 1 to 16, wherein the skin of the subject has no lesions.

19. The compound for use or composition for use according to any one of claims 1 to 11 , wherein the skin of the subject is infected or colonized with Staphylococcus aureus and the skin has lesions.

20. The compound for use or composition for use according to any one of claims 1 to 11 , wherein the skin of the subject is not infected or colonized with Staphylococcus aureus and the skin has lesions.

21 . The compound for use or composition for use according to any one of claims 1 to 20, wherein the subject is a mammal, preferably a human.

22. The composition for use according to any one of claims 2 to 21 , wherein the composition is a composition for topical administration.

23. The composition for use according to any one of claims 2 to 22, wherein the composition further comprises a pharmaceutical or a cosmetic excipient, preferably selected from glycerol, propylene glycol, cetearyl alcohol, and paraffin.

24. The composition for use according to any one of claims 2 to 23, wherein the composition is a cosmetic composition or is a pharmaceutical composition.

25. The compound for use or composition for use according to any one of claims 1 to 24, wherein administration is as frequently as desired, such as at least once a week, preferably three times a week, preferably once a day, preferably twice a day (BID).

26. The compound for use or composition for use according to any one of claims 1 to 25, wherein the amount of endolysin per administration is at least 10ug/cm² skin.

27. The compound for use or composition for use according to any one of claims 1 to 26, wherein the TEWL is reduced by at least 10%, preferably at least 15%.