Bacteriophages, phage endolysins and antimicrobial peptides – the possibilities for their common use to combat infections and in the design of new drugs
More details
Hide details
Biological Threat Identification and Countermeasure Centre of the Military Institute of Hygiene and Epidemiology, Puławy, Poland
Corresponding author
Tomasz Mirski   

Biological Threat Identification and Countermeasure Centre of the Military Institute of Hygiene and Epidemiology, Puławy, Poland
Ann Agric Environ Med. 2019;26(2):203-209
The antibiotic resistance in many pathogenic bacteria has become a major clinical problem, therefore, the necessity arises to search for new therapeutic strategies. The most promising solution lies in bacteriophages, phage endolysins and antimicrobial peptides. The aim of this study is to review the possibilities for the common use of bacteriophages, phage endolysins and antimicrobial peptides, both in the form of combined therapies and new strategies for the production of peptide drugs. Bacteriophages are viruses that specifically infect and destroy pathogenic bacteria by penetration into bacterial cells, causing metabolism disorders and, consequently, cell lysis. Phage-encoded endolysins are bacteriolytic proteins produced at the end of the phage lytic cycle that destroy elements of bacterial cell wall and enable the release of phage progeny from host cells. Antimicrobial peptides (AMPs) constitute an element of the innate immunity of living organisms and are characterized by the activity against a broad spectrum of bacteria. In the literature, there are only a few reports on the direct interaction of bacteriophages, phage endolysins and antimicrobial peptides against pathogenic bacteria. In each of them, a synergistic effect was observed, and Phage-encoded antimicrobial peptides as a specific group of AMPs have were also discussed. Phage-display technique was also reviewed in terms of its applications to produce and deliver biologically active peptides. The literature data also suggest that bacteriophages, phage endolysins and antimicrobial peptides can be used in combined therapy, thus negating many of the limitations resulting from their specificity as a single antimicrobial agent.
Price NL, Goyette-Desjardins G, Nothaft H, Valguarnera E, Szymanski CM, Segura M, et al. Glycoengineered outer membrane vesicles: a novel platform for bacterial vaccines. Sci Rep. 2016; 6: 24931.
Feng Y, Jonker MJ, Moustakas I, Brul S, Ter Kuile BH. Dynamics of mutations during development of resistance by Pseudomonas aeruginosa against five antibiotics. Antimicrob Agents Chemother. 2016; 60(7): 4229–4236.
Durai R, Ng PC, Hoque H. Methicillin-resistant Staphylococcus aureus: an update. Aorn J. 2010; 91(5): 599–606.
Ackermann H-W. Bacteriophage electron microscopy. In: Łobocka M, Szybalski WT, editors. Advances in Virus Research. Bacteriophages, Part A, London; 2012. p. 1–32.
Ackermann H-W. 5500 phages examined in the electron microscope. Arch Virol. 2007; 152(2): 227–243.
Breitbart M, Rohwer F. Here a virus, there a virus, everywhere the same virus? Trends Microbiol. 2005; 13(6): 278–284.
Adriaenssens EM, Edwards R, Nash JHE, Mahadevan P, Seto D, Ackermann HW et al. Integration of genome and proteomic analyses in the classification of Siphoviridae family. Virology. 2015; 477: 144–154.
Harada LK, Silva EC, Campos WF, Del Fiol FS, Vila M, Dąbrowska K, et al. Biotechnological applications of bacteriophages. State of the art. Microbiol Res. 2018; 212–213: 38–58.
Górski A, Międzybrodzki R, Borysowski J, Weber-Dąbrowska B, Łobocka M, Fortuna W, et al. Bacteriophage therapy for the treatment of infections. Curr Opin Investig Drugs. 2009; 10(8): 766–774.
Hanlon GW. Bacteriophages: An appraisal of their role in the treatment of bacterial infections. Int J Antimicrob Agents. 2007; 30(2): 118–128.
Matsuzaki S, Rashel M, Uchiyama J, Sakurai S, Ujihara T, Kuroda M, et al. Bacteriophage therapy: a revitalized therapy against bacterial infectious diseases. J Infect Chemother. 2005; 11(5), 211–219.
Biswas B, Adhya S, Washart P, Paul B, Trostel AN, Powell B, et al. Bacteriophage therapy rescues mice bacteremic from a clinical isolate of vancomycin-resistant Enterococcus faecium. Infect Immun. 2002; 70(1): 204–210.
Capparelli R, Parlato M, Borriello G, Salvatore P, Iannelli D. Experimental phage therapy against Staphylococcus aureus in mice. Antimicrob Agents Chemother. 2007; 51(8): 2765–2773.
Wang J, Hu B, Xu M, Yan Q, Liu S, Zhu X, et al. Use of bacteriophage in the treatment of experimental animal bacteremia from imipenem-resistant Pseudomonas aeruginosa. Int J Mol Med. 2006; 17(2): 309–317.
Balogh B, Jones JB, Iriarte FB, Momol MT. Phage therapy for plant disease control. Curr Pharm Biotechnol. 2010; 11(1): 48–57.
Mahony J, McAuliffe O, Ross RP, van Sinderen D. Bacteriophages as biocontrol agents of food pathogens. Curr Opin Biotechnol. 2011; 22(2): 157–163.
Hunter P. The return of the phage. EMBO Rep. 2011; 13(1): 20–23.
Wolcott R. A Prospective, randomized, double-blind controlled study of WPP-201 for the safety and efficacy of treatment of venous leg ulcers (WPP-201). U.S. National Library of Medicine. (access: 2018.12.07).
Young R. Bacteriophage lysis: mechanism and regulation. Microbiol Rev. 1992; 56(3): 430–481.
Schmelcher M, Shabarova T, Eugster MR, Eichenseher F, Tchang VS, Banz M, et al. Rapid multiplex detection and differentiation of Listeria cells by use of fluorescent phage endolysin cell wall binding domains. Appl Environ Microbiol. 2010; 76(17): 5745–5756.
Korndorfer IP, Danzer J, Schmelcher M, Zimmer M, Skerra A, Loessner MJ. The crystal structure of the bacteriophage PSA endolysin reveals a unique fold responsible for specific recognition of Listeria cell walls. J Mol Biol. 2006; 364(4): 678–689.
Seltman G, Holst O. The bacterial cell wall. Springer Verlag (Berlin), 2001.
Briers Y, Walmagh M, Lavigne R. Use of bacteriophage endolysin EL188 and outer membrane permeabilizers against Pseudomonas aeruginosa. J Appl Microbiol. 2011; 110(3): 778–785.
Lai MJ, Lin NT, Hu A, Soo PC, Chen LK, Chen LH, et al. Antibacterial activity of Acinetobacter baumannii phage QAB2 endolysin (LysAB2) against both gram-positive and gram-negative bacteria. Appl Microbiol Biotechnol. 2011; 90(2): 529–539.
Lukacik P, Barnard TJ, Keller PW, Chaturvedi KS, Seddiki N, Fairman JW, et al. Structural engineering of a phage lysin that targets Gram-negative pathogens. Proc Natl Acad Sci U S A. 2012; 109(25): 9857–9862.
Broekaert WF, Cammue BPA, DeBolle MFC, Thevissen K, De Samblanx GW, Osborn RW. Antimicrobial peptides from plants. Crit Rev Plant Sci. 1997; 16(3): 297–323.
Ganz T, Lehrer RI. Antimicrobial peptides of vertebrates. Curr Opin Immunol. 1998; 10(1): 41–44.
Otvos Jr L. Antibacterial peptides isolated from insects. J Pept Sci. 2000; 6(10): 497–511.
Zasloff M. Antimicrobial peptides of multicellular organisms. Nature. 2002; 415(6870): 389–395.
Brodgen KA, Ackermann M, McCray Jr PB, Tack BF. Antimicrobial peptides in animals and their role in host defences. Int J Antimicrob Agents. 2003; 22(5): 465–478.
Bulet P, Stöcklin R, Menin L. Antimicrobial peptides: from invertebrates to vertebrates. Immunol Rev. 2004; 198(1): 169–184.
Wang G, Li X, Wang Z. APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Res. 2016; 44(D1): D1087-D1093.
Hancock REW. Cationic peptides: effectors in innate immunity and novel antimicrobials. Lancet Infect Dis. 2001; 1(3): 156–164.–....
Montesinos E. Antimicrobial peptides and plant disease control. FEMS Microbiol Lett. 2007; 270(1): 1–11.
Zaiou Z. Multifunctional antimicrobial peptides: therapeutic targets in several human diseases. J Mol Med (Berl). 2007; 85(4): 317–329.
Hoskin DW, Ramamoorthy A. Studies on anticancer activities of antimicrobial peptides. Biochim. Biophys. Acta. 2008; 1778(2): 357–375.
Auvynet C, Rosentein Y. Multifunctional host defense peptides: Antimicrobial peptides, the small yet big players in innate and adaptive immunity. FEBS J. 2009; 276(22): 6497–6508.
Lai Y, Gallo RL. AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense. Trends Immunol. 2009; 30(3): 131–141.
Hancock REW, Patrzykat A. Clinical development of cationic antimicrobial peptides: from natural to novel antibiotics. Curr Drug Targets Infect Disord. 2002; 2(1): 79–83.
Hancock REW, Sahl HG. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol. 2006; 24(12): 1551–1557.
Peschel A, Sahl HG. The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nat Rev Microbiol. 2006; 4(7): 529–536.
Epand RM, Vogel HJ. Diversity of antimicrobial peptides and their mechanisms of action. Biochim Biophys Acta. 1999; 1462(1–2): 11–28.–....
Van’t Hof W, Veerman ECI, Helmerhorst EJ, Amerongen AVN. Antimicrobial peptides: properties and applicability. Biol Chem. 2001; 382(4): 597–619.
Huang HW. Molecular mechanism of antimicrobial peptides: The origin of cooperativity. Biochim Biophys Acta. 2006; 1758(9): 1292–1302.
Brodgen KA. Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol. 2005; 3(3): 238–250.
Nicolas P. Multifunctional host defense peptides: intracellular-targeting antimicrobial peptides. FEBS J. 2009; 276(22): 6483–6496.
Frick I-M, Nordin SL, Baumgarten M, Mörgelin M, Sørensen OE, Olin AI. Constitutive and inflammation-dependent antimicrobial peptides produced by epithelium are differentially processed and inactivated by the commensal Finegoldia magna and the pathogen Streptococcus pyogenes. J Immunol. 2011; 187(8): 4300–4309.
Thomassin J-L, Brannon JR, Gibbs BF, Gruenheid S, Le Moual H. OmpT outer membrane proteases of enterohemorrhagic and enteropathogenic Escherichia coli contribute differently to the degradation of human LL-37. Infect Immun. 2012; 80(2): 483–492.
Falord M, Karimova G, Hiron A, Msadek S. GraXSR proteins interact with the VraFG ABC transporter to form a five-component system required for cationic antimicrobial peptide sensing and resistance in Staphylococcus aureus. Antimicrob Agents Chemother. 2012; 56(2): 1047–1058.
Hiron A, Falord M, Valle J, Débarbouillé M, Msadek T. Bacitracin and nisin resistance in Staphylococcus aureus: a novel pathway involving the BraS/BraR two-component system (SA2417/SA2418) and both the BraD/BraE and VraD/VraE ABC transporters. Mol Microbiol. 2011; 81(3): 602–622.
Ernst CM, Kuhn S, Slavetinsky CJ, Krismer B, Heilbronner S, Gekeler C, et al. The lipid-modifying multiple peptide resistance factor is an oligomer consisting of distinct interacting synthase and flippase subunits. MBio. 2015; 6(1): e02340–14.
Batoni G, Maisetta G, Esin S. Antimicrobial peptides and their interaction with biofilms of medically relevant bacteria. Biochim Biophys Acta. 2016; 1858(5): 1044–1060.
Matson JS, Yoo HJ, Hakansson K, Dirita VJ. Polymyxin B resistance in El Tor Vibrio cholerae requires lipid acylation catalyzed by MsbB. J Bacteriol. 2010; 192(8): 2044–2052.
Boll JM, Tucker AT, Klein DR, Beltran AM, Brodbelt JS, Davies BW, et al. Reinforcing lipid A acylation on the cell surface of Acinetobacter baumannii promotes cationic antimicrobial peptide resistance and desiccation survival. MBio. 2015; 6(3): e00478–15.
Martinez B, Obeso JM, Rodriguez A, Garcia P. Nisin-bacteriophage crossresistance in Staphylococcus aureus. Int J Food Microbiol. 2008; 122(3): 253–258.
Garcia P, Martinez B, Rodriguez L, Rodriguez A. Synergy between the phage endolysin LysH5 and nisin to kill Staphylococcus aureus in pasteurized milk. Int J Food Microbiol. 2010; 141(3): 151–155.
White R, Burgess DS, Manduru M, Bosso JA. Comparison of three different in vitro methods of detecting synergy: time-kill, checkerboard, and E test. Antimicrob Agents Chemother. 1996; 40(8): 1914–1918.
Peng S-Y, You R-I, Lai M-J, Lin N-T, Chen L-K, Chang K-C. Highly potent antimicrobial modified peptides derived from the Acinetobacter baumannii phage endolysin LysAB2. Sci Rep. 2017; 7(1): 11477.
Parisien A, Allain B, Zhang J, Mandeville R, Lan CQ. Novel alternatives to antibiotics: bacteriophages, bacterial cell wall hydrolases, and antimicrobial peptides. J Appl Microbiol. 2008; 104(1): 1–13.
Mendel S, Holbourn JM, Schouten JA, Bugg TDH. Interaction of the transmembrane domain of lysis protein E from bacteriophage φX174 with bacterial translocase MraY and peptidyl-prolyl isomerase SlyD. Microbiology. 2006; 152(Pt 10): 2959–2967.
Young R, Wang IN, Roof WD. Phages will out: strategies of host cell lysis. Trends Microbiol. 2000; 8(3): 120–128.
Bernhardt TG, Wang IN, Struck DK, Young R. Breaking free: ‘‘protein antibiotics’’ and phage lysis. Res Microbiol. 2002; 153(8): 493–501.
Yu S, Peng W, Si W, Yin L, Liu S, Liu H, et al. Enhancement of bacteriolysis of the shuffled phage PhiX174 gene E. Virol J. 2011; 8(1): 206.
Ghequire MGK, De Mot R. The tailocin tale: peeling off phage tails. Trends Microbiol. 2015; 23(10): 587–590.
Noirclerc-Savoye M, Flayhan A, Pereira C, Gallet B, Gans P, Ebel C, et al. Tail proteins of phage T5: investigation of the effect of the His6-tag position, from expression to crystallisation. Protein Expr Purif. 2015; 109: 70–78.
Granell M, Namura M, Alvira S, Garcia-Doval C, Singh AK, Gutsche I, et al. Crystallization of the carboxy-terminal region of the bacteriophage T4 proximal long tail fibre protein gp34. Acta Crystallogr F Struct Biol Commun. 2014; 70(Pt 7): 970–975.
Hockett KL, Renner T, Baltrus DA. Independent co-option of a tailed bacteriophage into a killing complex in Pseudomonas. MBio. 2015; 6(4): e00452.
Liu J, Chen P, Zheng C, Huang YP. Characterization of maltocin P28, a novel phage tail-like bacteriocin from Stenotrophomonas maltophilia. Appl Environ Microbiol. 2013;79(18): 5593–5600.
Gebhart D, Lok S, Clare S, Tomas M, Stares M, Scholl D et al. A modified R-type bacteriocin specifically targeting Clostridium difficile prevents colonization of mice without affecting gut microbiota diversity. MBio. 2015; 6(2): e02368–14.
Smith GP. Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science. 1985; 228(4705): 1315–1317.
Pande J, Szewczyk MM, Grover AK. Phage display: concept, innovations, applications and future. Biotechnol Adv. 2010; 28(6): 849–858.
Hamzeh-Mivehroud M, Alizadeh AA, Morris MB, Church WB, Dastmalchi S. Phage display as a technology delivering on the promise of peptide drug discovery. Drug Discov Today. 2013; 18(23–24): 1144–1157.
Molek P, Strukelj B, Bratkovic T. Peptide phage display as a tool for drug discovery: targeting membrane receptors. Molecules. 2011; 16(1): 857–887.
Christensen DJ, Gottlin EB, Benson RE, Hamilton PT. Phage display for target-based antibacterial drug discovery. Drug Discov Today. 2001; 6(14): 721–727.
Sanschagrin F, Levesque RC. A specific peptide inhibitor of the class B metallo-β-lactamase L-1 from Stenotrophomonas maltophilia identified using phage display. J Antimicrob Chemother. 2005; 55(2): 252–255.
Grøn H, Hyde-DeRuyscher R. Peptides as tools in drug discovery. Curr Opin Drug Disc. 2000; 3(5): 636–645.
Thomas CJ, Sharma S, Kumar G, Visweswariah SS, Surolia A. Biopanning of endotoxin-specific phage displayed peptides. Biochem Biophys Res Commun. 2003; 307(1): 133–138.
Tao J, Wendler P, Connelly G, Lim A, Zhang J, King M, et al. Drug target validation: lethal infection blocked by inducible peptide. Proc Natl Acad Sci U S A. 2000; 97(2): 783–786.
Pini A, Giuliani A, Falciani C, Runci Y, Ricci C, Lelli B, et al. Antimicrobial activity of novel dendrimeric peptides obtained by phage display selection and rational modification. Antimicrob Agents Chemother. 2005; 49(7): 2665–2672.
Giuliani A, Pirri G, Nicoletto SF. Antimicrobial peptides: an overview of a promising class of therapeutics. Cent Eur J Biol. 2007; 2(1): 1–33.
Lee CC, MacKay JA, Fréchet JMJ, Szoka FC. Designing dendrimers for biological applications. Nat Biotechnol. 2005; 23(12): 1517–1526.
Journals System - logo
Scroll to top