Enzyme-based treatment of skin and soft tissue infections

Authors: Š. Kobzová 1;  L. Vacek 1,2;  B. Lipový 3;  M. Hanslianová 4;  L. Vojtová 5;  L. Janda 1
Authors‘ workplace: Oddělení infekčních chorob a preventivní medicíny, Výzkumný ústav veterinárního lékařství, Brno 1;  Mikrobiologický ústav Fakultní nemocnice u sv. Anny v Brně a Lékařské fakulty Masarykovy univerzity, Brno 2;  Klinika popálenin a rekonstrukční chirurgie, Fakultní nemocnice Brno 3;  Oddělení klinické mikrobiologie, Fakultní nemocnice Brno 4;  Pokročilé biomateriály, CEITEC – Středoevropský technologický institut, Vysoké učení technické v Brně 5
Published in: Epidemiol. Mikrobiol. Imunol. 70, 2021, č. 1, s. 52-61
Category: Review Article


Inflammatory diseases of the skin and soft tissues are an important group of human infections. The most common causes are the bacteria Staphylococcus aureus and Streptococcus pyogenes. Given the growing resistance of these pathogens to antimicrobials, the current research focuses on the search for novel therapeutic options that would be effective against infections refractory to conventional antimicrobials. A promising alternative is the use of enzyme-based antimicrobials (enzybiotics) that degrade the bacterial cell wall. They target the specific pathogen but do not affect the skin microbiome, thus helping the healing process. As enzymes can be poorly soluble, unstable, or subject to rapid elimination from the body, efforts are made to create biobetters, i.e., enzymes with improved characteristics. Emphasis is also put on the development of novel enzybiotic carriers or wound healing dressings with integrated enzymes.


skin and soft tissue infections – enzybiotics – antibacterial activity – resistance – biobetters – antibacterial wound dressing


1.      Ki V, Rotstein C. Bacterial skin and soft tissue infections in adults: A review of their epidemiology, pathogenesis, diagnosis, treatment and site of care. Can J Infect Dis Med Microbiol, 2008;19(2):173–184.

2.      Ray GT, Suaya JA, Baxter R. Microbiology of skin and soft tissue infections in the age of community-acquired methicillin-resistant Staphylococcus aureus. Diagn Microbiol Infect Dis, 2013;76(1):24–30.

3.      Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America. Clin Infect Dis, 2014;59(2).

4.      Tirupathi R, Areti S, Salim SA, et al. Acute bacterial skin and soft tissue infections: new drugs in ID armamentarium. J Community Hosp Intern Med Perspect, 2019;9(4):310–313.

5.      Eron LJ, Lipsky BA, Low DE, et al. Expert panel on managing skin and soft tissue infections. Managing skin and soft tissue infections: expert panel recommendations on key decision points. J Antimicrob Chemother, 2003;52(1):i3–17.

6.      Esposito S, Bassetti M, Concia E, et al. Italian Society of Infectious and Tropical Diseases. Diagnosis and management of skin and soft-tissue infections (SSTI). A literature review and consensus statement: an update. J Chemother, 2017;29(4):197–214.

7.      Esposito S, Bassetti M, Bonnet E, et al. Hot topics in the diagnosis and management of skin and soft-tissue infections. Int J Antimicrob Agents, 2016;48(1):19–26. doi:10.1016/j.ijantimicag.2016.04.011

8.      Johnson JK, Khoie T, Shurland S, et al. Skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus USA300 clone. Emerg Infect Dis, 2007; 13(8):1195–1200.

9.      Cong Y, Yang S, Rao X. Vancomycin resistant Staphylococcus aureus infections: A review of case updating and clinical features. J Adv Res, 2019;12(21):169–176.

10.    Owens CD, Stoessel K. Surgical site infections: epidemiology, microbiology and prevention. J Hosp Infect, 2008;70(Suppl 2):3–10.

11.    Moet GJ, Jones RN, Biedenbach DJ, et al. Contemporary causes of skin and soft tissue infections in North America, Latin America, and Europe: report from the SENTRY Antimicrobial Surveillance Program (1998–2004). Diagn Microbiol Infect Dis, 2007;57(1):7–13.

12.    Sader HS, Farrell DJ, Jones RN. Antimicrobial susceptibility of Gram-positive cocci isolated from skin and skin-structure infections in European medical centres. Int J Antimicrob Agents, 2010;36(1):28–32.

13.    Morrissey I, Leakey A, Northwood JB. In vitro activity of ceftaroline and comparator antimicrobials against European and Middle East isolates from complicated skin and skin-structure infections collected in 2008–2009. Int J Antimicrob Agents, 2012;40(3):227–234.

14.    Mahmoudi H, Bahador A, Pourhajibagher M, et al. Antimicrobial Photodynamic Therapy: An Effective Alternative Approach to Control Bacterial Infections. Journal of Lasers in Medical Sciences, 2018;9(3):154–160.

15.    Dakal TC, Kumar A, Majumdar RS, et al. Mechanistic Basis of Antimicrobial Actions of Silver Nanoparticles. Frontiers in Microbiology, 2016;7.

16.    Mulani MS, Kamble EE, Kumkar SN, Tawre MS, Pardesi KR. Emerging Strategies to Combat ESKAPE Pathogens in the Era of Antimicrobial Resistance: A Review. Frontiers in microbiology, 2019;10:539. Dostupný na www: https://doi.org/10.3389/fmicb.2019.00539.

17.    Assis, LM, Nedeljković M, Dessen A. New strategies for targeting and treatment of multi-drug resistant Staphylococcus aureus. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy, 2017;31:1–14.

18.    Domingo-Calap P, Delgado-Martínez J. Bacteriophages: Protagonists of a Post- Antibiotic Era. Antibiotics, 2018;7(3).

19.    Borysowski J, Weber-Dąbrowska B, Górski A. Bacteriophage Endolysins as a Novel Class of Antibacterial Agents. Experimental Biology and Medicine, 2006;231(4):366–377.

20.    Vollmer W. Structural variation in the glycan strands of bacterial peptidoglycan. FEMS Microbiology Reviews, 2008;32(2):287–306.

21.    Pellegrino L, Tirelli A. A sensitive HPLC method to detect hen‘s egg white lysozyme in milk and dairy products. International Dairy Journal, 2000;10(7):435–442.

22.    Aminlari L, Mohammadi Hashemi M, Aminlari M. Modified Lysozymes as Novel Broad Spectrum Natural Antimicrobial Agents in Foods. Journal of Food Science, 2014;79(6):1077–1090.

23.    Schuhardt VT, Schindler CA. Lysostaphin therapy in mice infected with Staphylococcus aureus. J Bacteriol, 1964;88(3):815–816.

24.    Cropp CB, Harrison EF. The in vitro effect of lysostaphin on clinical isolates of Staphylococcus aureus. Canadian Journal of Microbiology, 1964;10(6):823–828.

25.    Zygmunt WA, Browder HP, Tavormina PA. Lytic action of lysostaphin on susceptible and resistant strains of staphylococcus aureus. Canadian Journal of Microbiology, 1967;13(7):845–853.

26.    Quickel KE, Selden R, Caldwell JR, et al. Efficacy and Safety of Topical Lysostaphin Treatment of Persistent Nasal Carriage of Staphylococcus aureus. Applied Microbiology, 1971;22(3):446–450.

27.    Stark FR, Thornsvard C, Flannery EP, et al. Systemic lysostaphin in man – Apparent antimicrobial activity in a neutropenic patient. N. Engl. J. Med, 1974;291:239–240.

28.    Recsei PA, Gruss AD, Novick RP. Cloning, sequence, and expres­sion of the lysostaphin gene from Staphylococcus simulans. Proceedings of the National Academy of Sciences, 1987; 84(5):1127–1131.

29.    Gargis SR, Heath HE, LeBlanc PA, et al. Inhibition of the Activity of Both Domains of Lysostaphin through Peptidoglycan Modification by the Lysostaphin Immunity Protein. Applied and Environmental Microbiology, 2010;76(20):6944–6946.

30.    Hegarty JW, Guinane CM, Ross RP, et al. Bacteriocin production: a relatively unharnessed probiotic trait? F1000Research, 2016;5.

31.    Fahim HA, Khairalla AS, El-Gendy AO. „Nanotechnology: A Valuable Strategy to Improve Bacteriocin Formulations.“ Frontiers in Microbiology, 2016;7. Dostupný na www: http://dx.doi.org/10.3389/fmicb.2016.01385.

32.    Schmelcher M, Loessner MJ. Application of bacteriophages for detection of foodborne pathogens. Bacteriophage, 2014;4(2).

33.    Nelson D, Loomis L, Fischetti VA. Prevention and elimination of upper respiratory colonization of mice by group A streptococci by using a bacteriophage lytic enzyme. Proceedings of the National Academy of Sciences, 2001;98(7):4107–4112.

34.    Rashel M, Uchiyama J, Ujihara T, et al. Efficient Elimination of Multidrug‐Resistant Staphylococcus aureus by Cloned Lysin Derived from Bacteriophage φMR11. The Journal of Infectious Diseases, 2007;196(8):1237–1247.

35.    Lood R, Raz A, Molina H, et al. A highly active and negatively charged Streptococcus pyogenes lysin with a rare D-alanyl-L-alanine endopeptidase activity protects mice against streptococcal bacteremia. Antimicrob Agents Chemother, 2014;58(6):3073–3084.

36.    Oliveira H, São-José C, Azeredo J. Phage-Derived Peptidoglycan Degrading Enzymes: Challenges and Future Prospects for In Vivo Therapy. Viruses, 2018;10(6).

37.    Djurkovic S, Loeffler JM, Fischetti VA. Synergistic Killing of Streptococcus pneumoniae with the Bacteriophage Lytic Enzyme Cpl-1 and Penicillin or Gentamicin Depends on the Level of Penicillin Resistance. Antimicrobial Agents and Chemotherapy, 2005;49(3):1225–1228.

38.    Callewaert L, Walmagh M, Michiels CW, et al. Food applications of bacterial cell wall hydrolases. Current Opinion in Biotechnology, 2011;22(2):164–171.

39.    Schmelcher M, Donovan DM, Loessner MJ. Bacterio­phage endolysins as novel antimicrobials. Future Microbiology, 2012;7(10):1147–1171.

40.    Obeso JM, Martínez B, Rodríguez A, et al. Lytic activity of the recombinant staphylococcal bacteriophage ΦH5 endolysin active against Staphylococcus aureus in milk. International Journal of Food Microbiology, 2008;128(2):212–218.

41.    de Vries J, Harms K, Broer I, et al. The Bacteriolytic Activity in Transgenic Potatoes Expressing a Chimeric T4 Lysozyme Gene and the Effect of T4 Lysozyme on Soil- and Phytopathogenic Bacteria. Systematic and Applied Microbiology, 1999;22(2):280–286.

42.    Kumar JK. Lysostaphin: an antistaphylococcal agent. Applied Microbiology and Biotechnology, 2008;80(4):555–561.

43.    Dams D, Briers Y. Enzybiotics: Enzyme-Based Antibacterials as Therapeutics. In Labrou, N. (ed.). Therapeutic Enzymes: Function and Clinical Implications, 2019.

44.    Grishin AV, Lavrova NV, Lyashchuk AM, et al. The Influence of Dimerization on the Pharmacokinetics and Activity of an Antibacterial Enzyme Lysostaphin. Molecules, 2019;24(10).

45.    São-José C. Engineering of Phage-Derived Lytic Enzymes: Improving Their Potential as Antimicrobials. Antibiotics, 2018;7(2).

46.    Saravanan SR, Paul VD, George S, et al. Properties and mutation studies of a bacteriophage-derived chimeric recombinant staphylolytic protein P128. Bacteriophage, 2014;3(3).

47.    Fischetti VA. Bacteriophage lytic enzymes: novel anti-infectives. Trends in Microbiology, 2005;13(10):491–496.

48.    Haddad Kashani H, Schmelcher M, Sabzalipoor H, et al. Recombinant Endolysins as Potential Therapeutics against Antibiotic-Resistant Staphylococcus aureus: Current Status of Research and Novel Delivery Strategies. Clinical Microbiology Reviews, 2017;31(1): e00071–17.

49.    Guariglia-Oropeza V, Helmann JD. Bacillus subtilis σ V Confers Lysozyme Resistance by Activation of Two Cell Wall Modification Pathways, Peptidoglycan O-Acetylation and d-Alanylation of Teichoic Acids. Journal of Bacteriology, 2011;193(22):6223– 6232.

50.    Herbert S, Bera A, Nerz C, et al. Molecular Basis of Resistance to Muramidase and Cationic Antimicrobial Peptide Activity of Lysozyme in Staphylococci. PLoS Pathogens, 2007;3(7):07-PLPA-RA-0107.

51.    Davis KM, Akinbi HT, Standish AJ, et al. Resistance to Mucosal Lysozyme Compensates for the Fitness Deficit of Peptidoglycan Modifications by Streptococcus pneumoniae. PLoS Pathogens, 2008;4(12).

52.    Bera A, Herbert S, Jakob A, et al. Why are pathogenic staphylococci so lysozyme resistant? The peptidoglycan O-acetyltransferase OatA is the major determinant for lysozyme resistance of Staphylococcus aureus. Molecular Microbiology, 2005;55(3):778–787.

53.    Grundling AD, Missiakas M, Schneewind O. Staphylococcus aureus Mutants with Increased Lysostaphin Resistance. Journal of Bacteriology, 2006;188(17):6286–6297.

54.    Kusuma C, Jadanova A, Chanturiya T, et al. Lysostaphin-Resistant Variants of Staphylococcus aureus Demonstrate Reduced Fitness In Vitro and In Vivo. Antimicrobial Agents and Chemotherapy, 2007;51(2):475–482.

55.    Fenton M, McAuliffe O, O’Mahony J, et al. Recombinant bacterio­phage lysins as antibacterials. Bioengineered Bugs, 2010;1(1):9–16.

56.    Roach DR, Donovan DM. Antimicrobial bacteriophage-derived proteins and therapeutic applications. Bacteriophage, 2015;5(3).

57.    Szweda P, Schielmann M. Kotlowski R, et al. Peptidoglycan hydrolases-potential weapons against Staphylococcus aureus. Applied Microbiology and Biotechnology, 2012;96(5):1157–1174.

58.    Becker SC, Foster-Frey J, Donovan DM. The phage K lytic enzyme LysK and lysostaphin act synergistically to kill MRSA. FEMS Microbiology Letters, 2008;287(2):185–191.

59.    De Groot AS, Scott DW. Immunogenicity of protein therapeutics. Trends in Immunology, 2007;28(11):482–490.

60.    Fischetti VA. Bacteriophage lysins as effective antibacterials. Cur­rent Opinion in Microbiology, 2008;11(5):393–400.

61.    Loeffler JM, Djurkovic S, Fischetti VA. Phage Lytic Enzyme Cpl-1 as a Novel Antimicrobial for Pneumococcal Bacteremia. Infec­tion and Immunity, 2003;71(11):6199–6204.

62.    Abdelkader K, Gerstmans H, Saafan A, et al. The Preclinical and Clinical Progress of Bacteriophages and Their Lytic Enzymes: The Parts are Easier than the Whole. Viruses, 2019;11(2).

63.    Jun SY, Jang IJ, Yoon S, et al. Pharmacokinetics and Tolerance of the Phage Endolysin- Based Candidate Drug SAL200 after a Single Intravenous Administration among Healthy Volunteers. Antimicrobial Agents and Chemotherapy, 2017;61(6): e02629–02716.

64.    Gondil VS, Harjai K, Chhibber S. Endolysins as emerging alternative therapeutic agents to counter drug-resistant infections. Int. J. Antimicrob. Agents, 2020;55(2).

65.    Pinto AM, Cerqueira MA, Bañobre-Lópes M, et al. Bacteriopha­ges for Chronic Wound Treatment: From Traditional to Novel Delivery Systems. Viruses, 2020;12(2).

66.    Pham DT, Tiyaboonchai W. Fibroin nanoparticles: a promising drug delivery system. Drug Delivery, 2020;27(1):431–448.

67.    Solanki K, Grover N, Downs P, et al. Enzyme-Based Listericidal Nanocomposites. Scientific Reports, 2013;3(1).

68.    Cui F, Li G, Huang J, et al. Development of chitosan-collagen hydrogel incorporated with lysostaphin (CCHL) burn dressing with anti-methicillin-resistant Staphylococcus aureus and promotion wound healing properties. Drug Delivery, 2010;18(3):173–180.

69.    Bai J, Yang E, Chang PS, et al. Preparation and characterization of endolysin-containing liposomes and evaluation of their antimicrobial activities against gram-negative bacteria. Enzyme and Microbial Technology, 2019;128:40–48.

70.    Johnson CT, García AJ. Scaffold-based Anti-infection Strategies in Bone Repair. Annals of Biomedical Engineering, 2015;43(3):515–528.

71.    A ter Boo GJ, Grijpma DW, Moriarty TF, et al. Antimicrobial delivery systems for local infection prophylaxis in orthopedic- and trauma surgery. Biomaterials, 2015;52:113–125.

72.    Miao J, Pangule RC, Paskaleva EE, et al. lysostaphin-functionalized cellulose fibers with antistaphylococcal activity for wound healing applications. Biomaterials, 2011;32(36):9557–9567.

73.    Cui H, Yuan L, Lin L. Novel chitosan film embedded with liposome-encapsulated phage for biocontrol of Escherichia coli O157: H7 in beef. Carbohydrate Polymers, 2017;177:156–164.

74.    Desbois AP, Gemmell CG, Coote PJ. In vivo efficacy of the antimicrobial peptide ranalexin in combination with the endopeptidase lysostaphin against wound and systemic methicillin-resistant Staphylococcus aureus (MRSA) infections.“ Int. J. Antimicrob. Agents, 2010;35(6):559–565.

75.    Tegos G, Mylonakis E. Antimicrobial drug discovery: Emerging strategies. Advances in Molecular and Cellular Microbiology (CABI), 2012;p. X, 357.

76.    Johnson CT, Wroe JA, Agarwal R, et al. Hydrogel delivery of lysostaphin eliminates orthopedic implant infection by Staphylococcus aureus and supports fracture healing. Proceedings of the National Academy of Sciences, 2018;115(22).

Hygiene and epidemiology Medical virology Clinical microbiology

Article was published in

Epidemiology, Microbiology, Immunology

Issue 1

2021 Issue 1

Most read in this issue
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account