Exploration of Drug Science

Table 1. Summary of results from previous studies combining bacteriophage/bacteriophage endolysins and AMPs.

AMP + bacteriophage/lysin combination	Target bacteria	Outcome	Reference
FK13, FK16 (AMPs) + endolysin LysPB32	Polymyxin B-resistant Salmonella Typhimurium	The combination decreased the MIC values against the test bacteria. Enhanced reduction of bacterial growth in broth culture.	[19]
1. Polymyxin B + T7L endolysin 2. Colistin + T7L endolysin 3. Nisin + T4L endolysin	Pseudomonas aeruginosa, Staphylococcus aureus	All three combinations exhibited synergism to eradicate the biofilms of the respective bacteria.	[18]
R8K (AMP) + endolysin Lys11 (phage ϕ11)	Staphylococcus aureus	Increased bacterial killing due to increased binding of lysin to the bacterial cell wall.	[15]
Nisin + bacteriophage, SA46-CTH2	Staphylococcus aureus	Better bacterial killing in broth and milk. Enhanced biofilm eradication.	[17]
LL-37 + endolysin Ply2660	Enterococcus faecalis	Enhanced biofilm eradication.	[14]
Genetically engineered T7 phage expressed the AMP (1018)	Escherichia coli	Enhanced bacterial killing and biofilm eradication.	[20]

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AMPs: antimicrobial peptides; MIC: minimum inhibitory concentration.

Declarations

Author contributions

SN: Conceptualization, Investigation, Writing—original draft. KI: Writing—original draft. MAA: Conceptualization, Investigation, Writing—original draft, Writing—review & editing, Supervision. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

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References

Hansson K, Brenthel A. Imagining a post-antibiotic era: a cultural analysis of crisis and antibiotic resistance. Med Humanit. 2022;48:381–8. [DOI] [PubMed] [PMC]

Ahuatzin-Flores OE, Torres E, Chávez-Bravo E. Acinetobacter baumannii, a Multidrug-Resistant Opportunistic Pathogen in New Habitats: A Systematic Review. Microorganisms. 2024;12:644. [DOI] [PubMed] [PMC]

Ongenae V, Briegel A, Claessen D. Cell wall deficiency as an escape mechanism from phage infection. Open Biol. 2021;11:210199. [DOI] [PubMed] [PMC]

Stone E, Campbell K, Grant I, McAuliffe O. Understanding and Exploiting Phage-Host Interactions. Viruses. 2019;11:567. [DOI] [PubMed] [PMC]

Wang IN, Smith DL, Young R. Holins: the protein clocks of bacteriophage infections. Annu Rev Microbiol. 2000;54:799–825. [DOI] [PubMed]

Vollmer W, Joris B, Charlier P, Foster S. Bacterial peptidoglycan (murein) hydrolases. FEMS Microbiol Rev. 2008;32:259–86. [DOI] [PubMed]

Shen J, Zhou J, Fu H, Mu Y, Sun Y, Xu Y, et al. A Klebsiella pneumoniae bacteriophage and its effect on 1,3-propanediol fermentation. Process Biochem. 2016;51:1323–30. [DOI]

Holochová P, Růzicková V, Pantůcek R, Petrás P, Janisch R, Doskar J. Genomic diversity of two lineages of exfoliative toxin A-converting phages predominating in Staphylococcus aureus strains in the Czech Republic. Res Microbiol. 2010;161:260–7. [DOI] [PubMed]

Moravej H, Moravej Z, Yazdanparast M, Heiat M, Mirhosseini A, Moghaddam MM, et al. Antimicrobial Peptides: Features, Action, and Their Resistance Mechanisms in Bacteria. Microb Drug Resist. 2018;24:747–67. [DOI] [PubMed]

10.

Alisigwe CV, Ikpa CS, Otuonye UJ. Examining alternative approaches to antibiotic utilisation: A critical evaluation of phage therapy and antimicrobial peptides combination as potential alternatives. Microbe. 2025;6:100254. [DOI]

11.

Nayab S, Aslam MA, Rahman S, Sindhu Z, Sajid S, Zafar N, et al. A review of antimicrobial peptides: its function, mode of action and therapeutic potential. Int J Pept Res Ther. 2022;28:1–15. [DOI]

12.

Rima M, Rima M, Fajloun Z, Sabatier J, Bechinger B, Naas T. Antimicrobial Peptides: A Potent Alternative to Antibiotics. Antibiotics (Basel). 2021;10:1095. [DOI] [PubMed] [PMC]

13.

Rothong P, Leungtongkam U, Khongfak S, Homkaew C, Samathi S, Tandhavanant S, et al. Antimicrobial activity and synergistic effect of phage-encoded antimicrobial peptides with colistin and outer membrane permeabilizing agents against Acinetobacter baumannii. PeerJ. 2024;12:e18722. [DOI] [PubMed] [PMC]

14.

Zhang H, Zhang X, Liang S, Wang J, Zhu Y, Zhang W, et al. Bactericidal synergism between phage endolysin Ply2660 and cathelicidin LL-37 against vancomycin-resistant Enterococcus faecalis biofilms. NPJ Biofilms Microbiomes. 2023;9:16. [DOI] [PubMed] [PMC]

15.

Gouveia A, Pinto D, Veiga H, Antunes W, Pinho MG, São-José C. Synthetic antimicrobial peptides as enhancers of the bacteriolytic action of staphylococcal phage endolysins. Sci Rep. 2022;12:1245. [DOI] [PubMed] [PMC]

16.

Mirski T, Lidia M, Nakonieczna A, Gryko R. Bacteriophages, phage endolysins and antimicrobial peptides - the possibilities for their common use to combat infections and in the design of new drugs. Ann Agric Environ Med. 2019;26:203–9. [DOI] [PubMed]

17.

Duc HM, Son HM, Ngan PH, Sato J, Masuda Y, Honjoh K, et al. Isolation and application of bacteriophages alone or in combination with nisin against planktonic and biofilm cells of Staphylococcus aureus. Appl Microbiol Biotechnol. 2020;104:5145–58. [DOI] [PubMed]

18.

Tyagi JL, Gupta P, Ghate MM, Kumar D, Poluri KM. Assessing the synergistic potential of bacteriophage endolysins and antimicrobial peptides for eradicating bacterial biofilms. Arch Microbiol. 2024;206:272. [DOI] [PubMed]

19.

Kim J, Hasan M, Liao X, Ding T, Ahn J. Combined antimicrobial activity of short peptide and phage-derived endolysin against antibiotic-resistant Salmonella Typhimurium. Food Microbiol. 2025;125:104642. [DOI] [PubMed]

20.

Lemon DJ, Kay MK, Titus JK, Ford AA, Chen W, Hamlin NJ, et al. Construction of a genetically modified T7Select phage system to express the antimicrobial peptide 1018. J Microbiol. 2019;57:532–8. [DOI] [PubMed]

21.

Düring K, Porsch P, Mahn A, Brinkmann O, Gieffers W. The non-enzymatic microbicidal activity of lysozymes. FEBS Lett. 1999;449:93–100. [DOI] [PubMed]

22.

Thandar M, Lood R, Winer BY, Deutsch DR, Euler CW, Fischetti VA. Novel Engineered Peptides of a Phage Lysin as Effective Antimicrobials against Multidrug-Resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2016;60:2671–9. [DOI] [PubMed] [PMC]

23.

Li C, Jiang M, Khan FM, Zhao X, Wang G, Zhou W, et al. Intrinsic Antimicrobial Peptide Facilitates a New Broad-Spectrum Lysin LysP53 to Kill Acinetobacter baumannii In Vitro and in a Mouse Burn Infection Model. ACS Infect Dis. 2021;7:3336–44. [DOI] [PubMed]

24.

Szadkowska M, Olewniczak M, Kloska A, Jankowska E, Kapusta M, Rybak B, et al. A Novel Cryptic Clostridial Peptide That Kills Bacteria by a Cell Membrane Permeabilization Mechanism. Microbiol Spectr. 2022;10:e0165722. [DOI] [PubMed] [PMC]

25.

Vázquez R, Doménech-Sánchez A, Ruiz S, Sempere J, Yuste J, Albertí S, et al. Improvement of the Antibacterial Activity of Phage Lysin-Derived Peptide P87 through Maximization of Physicochemical Properties and Assessment of Its Therapeutic Potential. Antibiotics (Basel). 2022;11:1448. [DOI] [PubMed] [PMC]

26.

Vázquez R, Seoane-Blanco M, Rivero-Buceta V, Ruiz S, van Raaij MJ, García P. Monomodular Pseudomonas aeruginosa phage JG004 lysozyme (Pae87) contains a bacterial surface-active antimicrobial peptide-like region and a possible substrate-binding subdomain. Acta Crystallogr D Struct Biol. 2022;78:435–54. [DOI] [PubMed] [PMC]

27.

Heselpoth RD, Euler CW, Schuch R, Fischetti VA. Lysocins: Bioengineered Antimicrobials That Deliver Lysins across the Outer Membrane of Gram-Negative Bacteria. Antimicrob Agents Chemother. 2019;63:e00342-19. [DOI] [PubMed] [PMC]

28.

Wojciechowska M. Endolysins and membrane-active peptides: innovative engineering strategies against gram-negative bacteria. Front Microbiol. 2025;16:1603380. [DOI] [PubMed] [PMC]

29.

Latka A, Maciejewska B, Majkowska-Skrobek G, Briers Y, Drulis-Kawa Z. Bacteriophage-encoded virion-associated enzymes to overcome the carbohydrate barriers during the infection process. Appl Microbiol Biotechnol. 2017;101:3103–19. [DOI] [PubMed] [PMC]

30.

Tajer L, Paillart J, Dib H, Sabatier J, Fajloun Z, Khattar ZA. Molecular Mechanisms of Bacterial Resistance to Antimicrobial Peptides in the Modern Era: An Updated Review. Microorganisms. 2024;12:1259. [DOI] [PubMed] [PMC]

31.

Garvey M. Antimicrobial Peptides Demonstrate Activity against Resistant Bacterial Pathogens. Infect Dis Rep. 2023;15:454–69. [DOI] [PubMed] [PMC]

32.

Cole JN, Nizet V. Bacterial Evasion of Host Antimicrobial Peptide Defenses. Microbiol Spectr. 2016;4:10.1128/microbiolspec.VMBF-0006-2015. [DOI] [PubMed] [PMC]

33.

Hetta HF, Sirag N, Alsharif SM, Alharbi AA, Alkindy TT, Alkhamali A, et al. Antimicrobial Peptides: The Game-Changer in the Epic Battle Against Multidrug-Resistant Bacteria. Pharmaceuticals (Basel). 2024;17:1555. [DOI] [PubMed] [PMC]

34.

Assoni L, Milani B, Carvalho MR, Nepomuceno LN, Waz NT, Guerra MES, et al. Resistance Mechanisms to Antimicrobial Peptides in Gram-Positive Bacteria. Front Microbiol. 2020;11:593215. [DOI] [PubMed] [PMC]

35.

Yao K, Liu J, Sun R, Wang Y, Jiang Y, Wang T, et al. Enhancing the selectivity and conditional sensitivity of an antimicrobial peptide through cleavage simulations and homoarginine incorporation to combat drug-resistant bacteria. Sci Rep. 2025;15:21798. [DOI] [PubMed] [PMC]

36.

Meng H, Kumar K. Antimicrobial activity and protease stability of peptides containing fluorinated amino acids. J Am Chem Soc. 2007;129:15615–22. [DOI] [PubMed]

37.

Bellotti D, Remelli M. Lights and Shadows on the Therapeutic Use of Antimicrobial Peptides. Molecules. 2022;27:4584. [DOI] [PubMed] [PMC]

38.

Zaiou M, Nizet V, Gallo RL. Antimicrobial and protease inhibitory functions of the human cathelicidin (hCAP18/LL-37) prosequence. J Invest Dermatol. 2003;120:810–6. [DOI] [PubMed]

39.

Kang S, Nam SH, Lee B. Engineering Approaches for the Development of Antimicrobial Peptide-Based Antibiotics. Antibiotics (Basel). 2022;11:1338. [DOI] [PubMed] [PMC]

40.

Zaczek-Moczydłowska MA, Young GK, Trudgett J, Plahe C, Fleming CC, Campbell K, et al. Phage cocktail containing Podoviridae and Myoviridae bacteriophages inhibits the growth of Pectobacterium spp. under in vitro and in vivo conditions. PLoS One. 2020;15:e0230842. [DOI] [PubMed] [PMC]

41.

Nick JA, Dedrick RM, Gray AL, Vladar EK, Smith BE, Freeman KG, et al. Host and pathogen response to bacteriophage engineered against Mycobacterium abscessus lung infection. Cell. 2022;185:1860–74. [DOI] [PubMed] [PMC]

42.

Cisek AA, Dąbrowska I, Gregorczyk KP, Wyżewski Z. Phage Therapy in Bacterial Infections Treatment: One Hundred Years After the Discovery of Bacteriophages. Curr Microbiol. 2017;74:277–83. [DOI] [PubMed] [PMC]

43.

Diallo K, Dublanchet A. Benefits of Combined Phage-Antibiotic Therapy for the Control of Antibiotic-Resistant Bacteria: A Literature Review. Antibiotics (Basel). 2022;11:839. [DOI] [PubMed] [PMC]

44.

Ferriol-González C, Domingo-Calap P. Phages for Biofilm Removal. Antibiotics (Basel). 2020;9:268. [DOI] [PubMed] [PMC]

45.

Lin J, Du F, Long M, Li P. Limitations of Phage Therapy and Corresponding Optimization Strategies: A Review. Molecules. 2022;27:1857. [DOI] [PubMed] [PMC]

46.

Gogokhia L, Buhrke K, Bell R, Hoffman B, Brown DG, Hanke-Gogokhia C, et al. Expansion of Bacteriophages Is Linked to Aggravated Intestinal Inflammation and Colitis. Cell Host Microbe. 2019;25:285–99. [DOI] [PubMed] [PMC]

47.

Luong T, Salabarria A, Roach DR. Phage Therapy in the Resistance Era: Where Do We Stand and Where Are We Going? Clin Ther. 2020;42:1659–80. [DOI] [PubMed]

48.

Saha D, Mukherjee R. Ameliorating the antimicrobial resistance crisis: phage therapy. IUBMB Life. 2019;71:781–90. [DOI] [PubMed]

49.

Broncano-Lavado A, Santamaría-Corral G, Esteban J, García-Quintanilla M. Advances in Bacteriophage Therapy against Relevant MultiDrug-Resistant Pathogens. Antibiotics (Basel). 2021;10:672. [DOI] [PubMed] [PMC]

50.

Almaaytah A. ANTIMICROBIAL PEPTIDES AS POTENTIAL THERAPEUTICS: ADVANTAGES, CHALLENGES AND RECENT ADVANCES. Farmacia. 2022;70:991–1003. [DOI]

51.

Karlsson C, Andersson M, Collin M, Schmidtchen A, Björck L, Frick I. SufA—a novel subtilisin-like serine proteinase of Finegoldia magna. Microbiology (Reading). 2007;153:4208–18. [DOI] [PubMed]

52.

Costa F, Teixeira C, Gomes P, Martins MCL. Clinical Application of AMPs. Adv Exp Med Biol. 2019;1117:281–98. [DOI] [PubMed]

53.

Di L. Strategic approaches to optimizing peptide ADME properties. AAPS J. 2015;17:134–43. [DOI] [PubMed] [PMC]

54.

Dini I, De Biasi M, Mancusi A. An Overview of the Potentialities of Antimicrobial Peptides Derived from Natural Sources. Antibiotics (Basel). 2022;11:1483. [DOI] [PubMed] [PMC]

55.

Diallo K, Dublanchet A. A Century of Clinical Use of Phages: A Literature Review. Antibiotics (Basel). 2023;12:751. [DOI] [PubMed] [PMC]

56.

Yang Q, Le S, Zhu T, Wu N. Regulations of phage therapy across the world. Front Microbiol. 2023;14:1250848. [DOI] [PubMed] [PMC]

57.

Miedzybrodzki R, Hoyle N, Zhvaniya F, Łusiak-Szelachowska M, Weber-Dabrowska B, Łobocka M, et al. Current updates from the long-standing phage research centers in Georgia, Poland, and Russia. In: Harper DR, Abedon ST, Burrowes BH, McConville ML, editors. Bacteriophages. Cham: Springer; 2021.

58.

Abedon ST, Kuhl SJ, Blasdel BG, Kutter EM. Phage treatment of human infections. Bacteriophage. 2011;1:66–85. [DOI] [PubMed] [PMC]

59.

Jones JD, Trippett C, Suleman M, Clokie MRJ, Clark JR. The Future of Clinical Phage Therapy in the United Kingdom. Viruses. 2023;15:721. [DOI] [PubMed] [PMC]

60.

Pirnay J, Verbeken G, Ceyssens P, Huys I, De Vos D, Ameloot C, et al. The Magistral Phage. Viruses. 2018;10:64. [DOI] [PubMed] [PMC]

61.

Lin R, Fabijan A, Attwood L, Iredell J. State of the regulatory affair: regulation of phage therapy in Australia. Capsid Tail. 2019.

62.

Furfaro LL, Payne MS, Chang BJ. Bacteriophage Therapy: Clinical Trials and Regulatory Hurdles. Front Cell Infect Microbiol. 2018;8:376. [DOI] [PubMed] [PMC]

63.

United States Food and Drug Administration, Center for Biologics Evaluation and Research, National Institute of Allergy and Infectious Diseases. Science and regulation of bacteriophage therapy; 2021 Aug 31; Washington, US.

64.

European Medicines Agency. The European Regulatory System for Medicines. Amsterdam: European Medicines Agency; 2016.