Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Antimicrobial peptides: structure, functions and translational applications

Abstract

Novel solutions to combat the rapid evolution of antimicrobial resistance in human and animal pathogens are urgently required. Antimicrobial peptides (AMPs) represent promising therapeutic molecules, as they exhibit structural nuances and distinct molecular targets against pathogenic microorganisms. In this Review, we explore the multifaceted structural nature of AMPs and advanced structural conformations, discuss the distinct mechanisms of action and explore novel targets. Additionally, we discuss resistance mechanisms, cross-resistance and innovative strategies for AMP design and optimization. We argue that gaining insight into novel AMP structural arrangements, targets and design optimization is crucial for the development of innovative therapies that can be translated into clinical as well as broader applications.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The complex role of AMPs during infection in animal and plant hosts and environments.
Fig. 2: Structures, mechanisms of action and distinctive targets of AMPs.
Fig. 3: AMP design strategies and modifications.
Fig. 4: Diversity of self-assembled structures of AMPs.

Similar content being viewed by others

References

  1. Blake, K. L. & O’Neill, A. J. Transposon library screening for identification of genetic loci participating in intrinsic susceptibility and acquired resistance to antistaphylococcal agents. J. Antimicrob. Chemother. 68, 12–16 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Hancock, R. E. W. Peptide antibiotics. Lancet 349, 418–422 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Mookherjee, N. & Hancock, R. E. W. Cationic host defence peptides: innate immune regulatory peptides as a novel approach for treating infections. Cell. Mol. Life Sci. 64, 922–933 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Schwessinger, B. & Zipfel, C. News from the frontline: recent insights into PAMP-triggered immunity in plants. Curr. Opin. Plant Biol. 11, 389–395 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Chaudhary, S., Ali, Z. & Mahfouz, M. Molecular farming for sustainable production of clinical-grade antimicrobial peptides. Plant Biotechnol. J. 22, 2282–2300 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. De Breij, A. et al. The antimicrobial peptide SAAP-148 combats drug-resistant bacteria and biofilms. Sci. Transl Med. 10, eaan4044 (2018). This study identifies SAAP-148 as a promising AMP capable of eradicating multidrug-resistant bacteria, biofilms and persister cells, with minimal resistance potential, paving the way for innovative treatments against antibiotic-resistant infections.

    Article  PubMed  Google Scholar 

  7. Bacalum, M. & Radu, M. Cationic antimicrobial peptides cytotoxicity on mammalian cells: an analysis using therapeutic index integrative concept. Int. J. Pept. Res. Ther. 21, 47–55 (2015).

    Article  CAS  Google Scholar 

  8. Brown, P. & Dawson, M. J. Development of new polymyxin derivatives for multi-drug resistant Gram-negative infections. J. Antibiot. 70, 386–394 (2017).

    Article  CAS  Google Scholar 

  9. Hancock, R. E. W. & Lehrer, R. Cationic peptides: a new source of antibiotics. Trends Biotechnol. 16, 82–88 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Zasloff, M. Magainins, a class of antimicrobial peptides from Xenopus skin: isolation, characterization of two active forms, and partial cDNA sequence of a precursor. Proc. Natl Acad. Sci. USA 84, 5449–5453 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mandard, N., Bulet, P., Caille, A., Daffre, S. & Vovelle, F. The solution structure of gomesin, an antimicrobial cysteine-rich peptide from the spider. Eur. J. Biochem. 269, 1190–1198 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Selsted, M. E. et al. Indolicidin, a novel bactericidal tridecapeptide amide from neutrophils. J. Biol. Chem. 267, 4292–4295 (1992).

    Article  CAS  PubMed  Google Scholar 

  13. Tang, Y. Q. et al. A cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated α-defensins. Science 286, 498–502 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Craik, D. J., Daly, N. L., Bond, T. & Waine, C. Plant cyclotides: a unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif. J. Mol. Biol. 294, 1327–1336 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Sneideris, T. et al. Targeting nucleic acid phase transitions as a mechanism of action for antimicrobial peptides. Nat. Commun. 14, 7170 (2023). This article reveals that AMPs can induce phase transitions in bacterial nucleic acids, providing a novel mechanism for their antibacterial activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Seefeldt, A. C. et al. Structure of the mammalian antimicrobial peptide Bac7(1–16) bound within the exit tunnel of a bacterial ribosome. Nucleic Acids Res. 44, 2429–2438 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ghosh, A. et al. Indolicidin targets duplex DNA: structural and mechanistic insight through a combination of spectroscopy and microscopy. Chem. Med. Chem. 9, 2052–2058 (2014).

    Article  CAS  PubMed  Google Scholar 

  18. Koehbach, J. & Craik, D. J. The vast structural diversity of antimicrobial peptides. Trends Pharmacol. Sci. 40, 517–528 (2019).

    Article  CAS  PubMed  Google Scholar 

  19. Hsu, C. H. et al. Structural and DNA-binding studies on the bovine antimicrobial peptide, indolicidin: evidence for multiple conformations involved in binding to membranes and DNA. Nucleic Acids Res. 33, 4053–4064 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tsai, C. Y. et al. Helical structure motifs made searchable for functional peptide design. Nat. Commun. 13, 102 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wallace, B. A. Recent advances in the high-resolution structures of bacterial channels: gramicidin A. J. Struct. Biol. 121, 123–141 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Urry, D. W., Goodall, M. C., Glickson, J. D. & Mayers, D. F. The gramicidin A transmembrane channel: characteristics of head-to-head dimerized π(L,D) helices. Proc. Natl Acad. Sci. USA 68, 1907–1911 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Andersson, H. S. et al. The α-defensin salt-bridge induces backbone stability to facilitate folding and confer proteolytic resistance. Amino Acids 43, 1471–1483 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mani, R. et al. Membrane-bound dimer structure of a β-hairpin antimicrobial peptide from rotational-echo double-resonance solid-state NMR. Biochemistry 45, 8341–8349 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Mandard, N. et al. Solution structure of thanatin, a potent bactericidal and fungicidal insect peptide, determined from proton two-dimensional nuclear magnetic resonance data. Eur. J. Biochem. 256, 404–410 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Datta, S., Sham Ala, N., Gurunath, R. & Balaram, P. Observation of a mixed antiparallel and parallel β-sheet motif in the crystal structure of Boc-Ala-Ile-Aib-OMe. Int. J. Pept. Protein Res. 48, 209–214 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Zasloff, M. Antimicrobial peptides of multicellular organisms. Nature 415, 389–395 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. DeLorbe, J. E. et al. Thermodynamic and structural effects of conformational constraints in protein-ligand interactions. Entropic paradoxy associated with ligand preorganization. J. Am. Chem. Soc. 131, 16758–16770 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. He, J., Ghosh, P. & Nitsche, C. Biocompatible strategies for peptide macrocyclisation. Chem. Sci. 15, 2300–2322 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhao, J., Ge, G., Huang, Y., Hou, Y. & Hu, S. Q. Butelase 1-mediated enzymatic cyclization of antimicrobial peptides: improvements on stability and bioactivity. J. Agric. Food Chem. 70, 15869–15878 (2022).

    Article  CAS  PubMed  Google Scholar 

  31. Cardoso, M. H., de la Fuente-Nunez, C., Santos, N. C., Zasloff, M. A. & Franco, O. L. Influence of antimicrobial peptides on the bacterial membrane curvature and vice versa. Trends Microbiol. 7, 624–627 (2024). This article highlights how understanding the physico-chemical properties of bacterial membranes and their curvature can inform the design of more effective AMPs to combat antimicrobial resistance.

    Article  Google Scholar 

  32. Wu, M., Maier, E., Benz, R. & Hancock, R. E. W. Mechanism of interaction of different classes of cationic antimicrobial peptides with planar bilayers and with the cytoplasmic membrane of Escherichia coli†. Biochemistry 38, 7235–7242 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Powers, J. P. S., Tan, A., Ramamoorthy, A. & Hancock, R. E. W. Solution structure and interaction of the antimicrobial polyphemusins with lipid membranes. Biochemistry 44, 15504–155013 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. He, K., Ludtke, S. J., Heller, W. T. & Huang, H. W. Mechanism of alamethicin insertion into lipid bilayers. Biophys. J. 71, 2669–2679 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Song, C. et al. Crystal structure and functional mechanism of a human antimicrobial membrane channel. Proc. Natl Acad. Sci. USA 110, 4586–4591 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Santos, D. E. S., Pol-Fachin, L., Lins, R. D. & Soares, T. A. Polymyxin binding to the bacterial outer membrane reveals cation displacement and increasing membrane curvature in susceptible but not in resistant lipopolysaccharide chemotypes. J. Chem. Inf. Model. 57, 2181–2193 (2017).

    Article  CAS  PubMed  Google Scholar 

  37. Pokorny, A. & Almeida, P. F. F. Kinetics of dye efflux and lipid flip-flop induced by δ-lysin in phosphatidylcholine vesicles and the mechanism of graded release by amphipathic, α-helical peptides. Biochemistry 43, 8846–8857 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Bechinger, B. Structure and functions of channel-forming peptides: magainins, cecropins, melittin and alamethicin. J. Memb. Biol. 156, 197–211 (1997).

    Article  CAS  Google Scholar 

  39. Rai, D. K. & Qian, S. Interaction of the antimicrobial peptide aurein 1.2 and charged lipid bilayer. Sci. Rep. 7, 3719 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Gong, H. et al. How do antimicrobial peptides disrupt the lipopolysaccharide membrane leaflet of Gram-negative bacteria? J. Colloid Interface Sci. 637, 182–192 (2023).

    Article  CAS  PubMed  Google Scholar 

  41. Zampaloni, C. et al. A novel antibiotic class targeting the lipopolysaccharide transporter. Nature 625, 566–571 (2024). This article details the discovery of a novel antibiotic class targeting the bacterial LPS transporter, demonstrating potent activity against carbapenem-resistant A. baumannii.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kaur, H. et al. The antibiotic darobactin mimics a β-strand to inhibit outer membrane insertase. Nature 593, 125–129 (2021).

    Article  CAS  PubMed  Google Scholar 

  43. Makowski, M. et al. Activity modulation of the Escherichia coli F1FO ATP synthase by a designed antimicrobial peptide via cardiolipin sequestering. iScience 26, 107004 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mangano, K. et al. Inhibition of translation termination by the antimicrobial peptide drosocin. Nat. Chem. Biol. 19, 1082–1090 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kragol, G. et al. The antibacterial peptide pyrrhocoricin inhibits the ATPase actions of DnaK and prevents chaperone-assisted protein folding. Biochemistry 40, 3016–3026 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Liebscher, M. & Roujeinikova, A. Allosteric coupling between the lid and interdomain linker in DnaK revealed by inhibitor binding studies. J. Bacteriol. 191, 1456–1462 (2009).

    Article  CAS  PubMed  Google Scholar 

  47. Couto, M. A., Harwig, S. S. L. & Lehrer, R. I. Selective inhibition of microbial serine proteases by eNAP-2, an antimicrobial peptide from equine neutrophils. Infect. Immun. 61, 2991–2994 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ho, Y. H., Shah, P., Chen, Y. W. & Chen, C. S. Systematic analysis of intracellular-targeting antimicrobial peptides, bactenecin 7, hybrid of pleurocidin and dermaseptin, proline-arginine-rich peptide, and lactoferricin b, by using Escherichia coli proteome microarrays. Mol. Cell. Proteom. 15, 1837–1847 (2016).

    Article  CAS  Google Scholar 

  49. Chileveru, H. R. et al. Visualizing attack of Escherichia coli by the antimicrobial peptide human defensin 5. Biochemistry 54, 1767–1777 (2015).

    Article  CAS  PubMed  Google Scholar 

  50. Bisson-Filho, A. W. et al. FtsZ filament capping by MciZ, a developmental regulator of bacterial division. Proc. Natl Acad. Sci. USA 112, 2130–2138 (2015).

    Article  Google Scholar 

  51. Mora-Ochomogo, M. & Lohans, C. T. β-Lactam antibiotic targets and resistance mechanisms: from covalent inhibitors to substrates. RSC Med. Chem. 12, 1623–1639 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Motta, S. S., Cluzel, P. & Aldana, M. Adaptive resistance in bacteria requires epigenetic inheritance, genetic noise, and cost of efflux pumps. PLoS ONE 10, e0118464 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Ogawa, W., Onishi, M., Ni, R., Tsuchiya, T. & Kuroda, T. Functional study of the novel multidrug efflux pump KexD from Klebsiella pneumoniae. Gene 498, 177–182 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Billal, D. S., Feng, J., Leprohon, P., Légaré, D. & Ouellette, M. Whole genome analysis of linezolid resistance in Streptococcus pneumoniae reveals resistance and compensatory mutations. BMC Genomics 12, 512 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Cottell, J. L., Webber, M. A. & Piddock, L. J. V. Persistence of transferable extended-spectrum-β-lactamase resistance in the absence of antibiotic pressure. Antimicrob. Agents Chemother. 56, 4703–4706 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Spohn, R. et al. Integrated evolutionary analysis reveals antimicrobial peptides with limited resistance. Nat. Commun. 10, 4538 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Bauer, M. E. & Shafer, W. M. On the in vivo significance of bacterial resistance to antimicrobial peptides. Biochim. Biophys. Acta 1848, 3101–3111 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gunn, J. S., Ryan, S. S., Van Velkinburgh, J. C., Ernst, R. K. & Miller, S. I. Genetic and functional analysis of a PmrA–PmrB-regulated locus necessary for lipopolysaccharide modification, antimicrobial peptide resistance, and oral virulence of Salmonella enterica serovar typhimurium. Infect. Immun. 68, 6139–6146 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Nuri, R., Shprung, T. & Shai, Y. Defensive remodeling: how bacterial surface properties and biofilm formation promote resistance to antimicrobial peptides. Biochim. Biophys. Acta 1848, 3089–3100 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. Macfarlane, E. L. A., Kwasnicka, A., Ochs, M. M. & Hancock, R. E. W. PhoP–PhoQ homologues in Pseudomonas aeruginosa regulate expression of the outer-membrane protein OprH and polymyxin B resistance. Mol. Microbiol. 34, 305–316 (1999).

    Article  CAS  PubMed  Google Scholar 

  61. Campos, M. A. et al. Capsule polysaccharide mediates bacterial resistance to antimicrobial peptides. Infect. Immun. 72, 7107–7114 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Khondker, A. & Rheinstädter, M. C. How do bacterial membranes resist polymyxin antibiotics? Commun. Biol. 3, 77 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Wiedemann, I. et al. Specific binding of nisin to the peptidoglycan precursor lipid II combines pore formation and inhibition of cell wall biosynthesis for potent antibiotic activity. J. Biol. Chem. 276, 1772–1779 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Kovács, M. et al. A functional dlt operon, encoding proteins required for incorporation of d-alanine in teichoic acids in Gram-positive bacteria, confers resistance to cationic antimicrobial peptides in Streptococcus pneumoniae. J. Bacteriol. 188, 5797–5805 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Verheul, A., Russell, N. J., Van’T Hof, R., Rombouts, F. M. & Abee, T. Modifications of membrane phospholipid composition in nisin-resistant Listeria monocytogenes Scott A. Appl. Environ. Microbiol. 63, 3451–3457 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Jarvis, B. & Farr, J. Partial purification, specificity and mechanism of action of the nisin-inactivating enzyme from Bacillus cereus. Biochim. Biophys. Acta 227, 232–240 (1971).

    Article  CAS  PubMed  Google Scholar 

  67. Collins, B., Curtis, N., Cotter, P. D., Hill, C. & Ross, R. P. The ABC transporter AnrAB contributes to the innate resistance of Listeria monocytogenes to nisin, bacitracin, and various β-lactam antibiotics. Antimicrob. Agents Chemother. 54, 4416–4423 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kim, S. W. et al. Outer membrane vesicles from β-lactam-resistant Escherichia coli enable the survival of β-lactam-susceptible E. coli in the presence of β-lactam antibiotics. Sci. Rep. 8, 5402 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Trombley, M. P. et al. Phosphoethanolamine transferase LptA in Haemophilus ducreyi modifies lipid A and contributes to human defensin resistance in vitro. PLoS ONE 10, e0124373 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Blair, J. M. A., Zeth, K., Bavro, V. N. & Sancho-Vaello, E. The role of bacterial transport systems in the removal of host antimicrobial peptides in Gram-negative bacteria. FEMS Microbiol. Rev. 46, fuac032 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Sieprawska-Lupa, M. et al. Degradation of human antimicrobial peptide LL-37 by Staphylococcus aureus-derived proteinases. Antimicrob. Agents Chemother. 48, 4673–4679 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Stumpe, S., Schmid, R., Stephens, D. L., Georgiou, G. & Bakker, E. P. Identification of OmpT as the protease that hydrolyzes the antimicrobial peptide protamine before it enters growing cells of Escherichia coli. J. Bacteriol. 180, 4002–4006 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Sakenova, N. et al. Systematic mapping of antibiotic cross-resistance and collateral sensitivity with chemical genetics. Nat. Microbiol. 10, 202–216 (2025). This study uses chemical genetics to identify antibiotic cross-resistance and collateral sensitivity interactions in E. coli, significantly expanding the number of known interactions. The findings demonstrate that combining specific drug pairs can reduce resistance development.

    Article  CAS  PubMed  Google Scholar 

  74. Cherny, S. S., Chowers, M. & Obolski, U. Bayesian network modeling of patterns of antibiotic cross-resistance by bacterial sample source. Commun. Med. 3, 61 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Maron, B., Rolff, J., Friedman, J. & Hayouka, Z. Antimicrobial peptide combination can hinder resistance evolution. Microbiol. Spectr. 10, e0097322 (2022).

    Article  PubMed  Google Scholar 

  76. Wang, Z. et al. A naturally inspired antibiotic to target multidrug-resistant pathogens. Nature 601, 606–611 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. De Magalhães, C. S., Almeida, D. M., Barbosa, H. J. C. & Dardenne, L. E. A dynamic niching genetic algorithm strategy for docking highly flexible ligands. Inf. Sci. 289, 206–224 (2014).

    Article  Google Scholar 

  78. Fjell, C. D., Hiss, J. A., Hancock, R. E. W. & Schneider, G. Designing antimicrobial peptides: form follows function. Nat. Rev. Drug Discov. 11, 37–51 (2011).

    Article  PubMed  Google Scholar 

  79. Yoshida, M. et al. Using evolutionary algorithms and machine learning to explore sequence space for the discovery of antimicrobial peptides. Chem 4, 533–543 (2018).

    Article  CAS  Google Scholar 

  80. Loose, C., Jensen, K., Rigoutsos, I. & Stephanopoulos, G. A linguistic model for the rational design of antimicrobial peptides. Nature 443, 867–869 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Wang, X. et al. ProT‐Diff: a modularized and efficient strategy for de novo generation of antimicrobial peptide sequences by integrating protein language and diffusion models. Adv. Sci. 11, e2406305 (2024).

    Article  Google Scholar 

  82. Tucker, A. T. et al. Discovery of next-generation antimicrobials through bacterial self-screening of surface-displayed peptide libraries. Cell 172, 618–628 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Randall, J. R. et al. Adapting antibacterial display to identify serum-active macrocyclic peptide antibiotics. PNAS Nexus 2, pgad270 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Yamagami, S., Okada, Y., Kitano, Y. & Chiba, K. Peptide head-to-tail cyclization: a “molecular claw” approach. Eur. J. Org. Chem. 2021, 3133–3138 (2021).

    Article  CAS  Google Scholar 

  85. Chapman, R. N., Dimartino, G. & Arora, P. S. A highly stable short α-helix constrained by a main-chain hydrogen-bond surrogate. J. Am. Chem. Soc. 126, 12252–12253 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Lu, J. et al. d- and unnatural amino acid substituted antimicrobial peptides with improved proteolytic resistance and their proteolytic degradation characteristics. Front. Microbiol. 11, 563030 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Hicks, R. P., Bhonsle, J. B., Venugopal, D., Koser, B. W. & Magill, A. J. De novo design of selective antibiotic peptides by incorporation of unnatural amino acids. J. Med. Chem. 50, 3026–3036 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Meunier, B. Hybrid molecules with a dual mode of action: dream or reality? Acc. Chem. Res. 41, 69–77 (2008).

    Article  CAS  PubMed  Google Scholar 

  89. Wang, Z. et al. A cleavable chimeric peptide with targeting and killing domains enhances LPS neutralization and antibacterial properties against multi-drug resistant E. coli. Commun. Biol. 6, 1170 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Liu, L. et al. Self-assembled cationic peptide nanoparticles as an efficient antimicrobial agent. Nat. Nanotech. 4, 457–463 (2009).

    Article  CAS  Google Scholar 

  91. Lai, Z. et al. Self-assembling peptide dendron nanoparticles with high stability and a multimodal antimicrobial mechanism of action. ACS Nano 15, 15824–15840 (2021).

    Article  CAS  PubMed  Google Scholar 

  92. Chou, S. et al. Synthetic peptides that form nanostructured micelles have potent antibiotic and antibiofilm activity against polymicrobial infections. Proc. Natl Acad. Sci. USA 120, e2219679120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Fa, K. et al. In-membrane nanostructuring of cationic amphiphiles affects their antimicrobial efficacy and cytotoxicity: a comparison study between a de novo antimicrobial lipopeptide and traditional biocides. Langmuir 38, 6623–6637 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Greber, K. E. & Dawgul, M. Antimicrobial peptides under clinical trials. Curr. Top. Med. Chem. 17, 620–628 (2017).

    Article  CAS  PubMed  Google Scholar 

  95. Sheard, D. E., O’Brien-Simpson, N. M., Wade, J. D. & Separovic, F. Combating bacterial resistance by combination of antibiotics with antimicrobial peptides. Pur. Appl. Chem. 91, 199–209 (2019).

    Article  CAS  Google Scholar 

  96. Alaoui Mdarhri, H. et al. Alternatives therapeutic approaches to conventional antibiotics: advantages, limitations and potential application in medicine. Antibiotics 11, 1826 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Pfalzgraff, A., Brandenburg, K. & Weindl, G. Antimicrobial peptides and their therapeutic potential for bacterial skin infections and wounds. Front. Pharmacol. 9, 281 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Zhao, C., Yan, S., Luo, Y., Song, Y. & Xia, X. Analyzing resistome in soil and human gut: a study on the characterization and risk evaluation of antimicrobial peptide resistance. Front. Microbiol. 15, 1352531 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Jangir, P. K. et al. The evolution of colistin resistance increases bacterial resistance to host antimicrobial peptides and virulence. eLife 12, e84395 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Koh, A. J. J. et al. Bifunctional antibiotic hybrids: a review of clinical candidates. Front. Pharmacol. 14, 1158152 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Lei, J. et al. The antimicrobial peptides and their potential clinical applications. Am. J. Transl Res. 11, 3919–3931 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Shi, J., Chen, C., Wang, D., Wang, Z. & Liu, Y. The antimicrobial peptide LI14 combats multidrug-resistant bacterial infections. Commun. Biol. 5, 926 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Levin, M. et al. Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial. Lancet 356, 961–967 (2000).

    Article  CAS  PubMed  Google Scholar 

  104. Ivarsson, M. E., Leroux, J. C. & Castagner, B. Investigational new treatments for Clostridium difficile infection. Drug Discov. Today 20, 602–608 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. Lee, C. H. et al. Surotomycin versus vancomycin for Clostridium difficile infection: phase 2, randomized, controlled, double-blind, non-inferiority, multicentre trial. J. Antimicrob. Chemother. 71, 2964–2971 (2016).

    Article  CAS  PubMed  Google Scholar 

  106. Lee, S., Schefter, B. R., Taheri-Araghi, S. & Ha, B. Y. Modeling selectivity of antimicrobial peptides: how it depends on the presence of host cells and cell density. RSC Adv. 13, 34167–34182 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Michael Conlon, J., Galadari, S., Raza, H. & Condamine, E. Design of potent, non-toxic antimicrobial agents based upon the naturally occurring frog skin peptides, ascaphin-8 and peptide XT-7. Chem. Biol. Drug Des. 72, 58–64 (2008).

    Article  PubMed  Google Scholar 

  108. Morris, C. J. et al. Pegylation of antimicrobial peptides maintains the active peptide conformation, model membrane interactions, and antimicrobial activity while improving lung tissue biocompatibility following airway delivery. Antimicrob. Agents Chemother. 56, 3298–3308 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Cesaro, A., Lin, S., Pardi, N. & de la Fuente-Nunez, C. Advanced delivery systems for peptide antibiotics. Adv. Drug Deliv. Rev. 196, 114733 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. De Yang, B. et al. LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J. Exp. Med. 192, 1069–1074 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Rosenfeld, Y., Papo, N. & Shai, Y. Endotoxin (lipopolysaccharide) neutralization by innate immunity host-defense peptides: peptide properties and plausible modes of action. J. Biol. Chem. 281, 1636–1643 (2006).

    Article  CAS  PubMed  Google Scholar 

  112. Tang, D., Wang, G. & Zhou, J. M. Receptor kinases in plant–pathogen interactions: more than pattern recognition. Plant Cell 29, 618–637 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Romero, A., Alamillo, J. M. & García-Olmedo, F. Processing of thionin precursors in barley leaves by a vacuolar proteinase. Eur. J. Biochem. 243, 202–208 (1997).

    Article  CAS  PubMed  Google Scholar 

  114. Van De Velde, W. et al. Plant peptides govern terminal differentiation of bacteria in symbiosis. Science 327, 1122–1126 (2010).

    Article  PubMed  Google Scholar 

  115. Salzman, N. H., Ghosh, D., Huttner, K. M., Paterson, Y. & Bevins, C. L. Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 422, 522–526 (2003).

    Article  CAS  PubMed  Google Scholar 

  116. Franzenburg, S. et al. Distinct antimicrobial peptide expression determines host species-specific bacterial associations. Proc. Natl Acad. Sci. USA 110, 3730–3738 (2013).

    Article  Google Scholar 

  117. Braffman, N. R. et al. Structural mechanism of transcription inhibition by lasso peptides microcin J25 and capistruin. Proc. Natl Acad. Sci. USA 116, 1273–1278 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Mourtada, R. et al. Design of stapled antimicrobial peptides that are stable, nontoxic and kill antibiotic-resistant bacteria in mice. Nat. Biotech. 37, 1186–1197 (2019). This article highlights the ability of peptide PEP-1 to form various nanostructures and secondary structures through controlled changes in pH, concentration and temperature, showcasing its potential for biomedical applications.

    Article  CAS  Google Scholar 

  119. Liu, T. et al. Effect of N-methylated and fatty acid conjugation on analogs of antimicrobial peptide Anoplin. Eur. J. Pharm. Sci. 152, 105453 (2020).

    Article  CAS  PubMed  Google Scholar 

  120. Ghosh, G. et al. Control over multiple nano- and secondary structures in peptide self-assembly. Angew. Chem. Int. Ed. 61, e202113403 (2022).

    Article  CAS  Google Scholar 

  121. Salinas, N. et al. The amphibian antimicrobial peptide uperin 3.5 is a cross-α/cross-β chameleon functional amyloid. Proc. Natl Acad. Sci. USA 118, e2014442118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Tai, H. M. et al. Dietary supplementation of recombinant antimicrobial peptide Epinephelus lanceolatus piscidin improves growth performance and immune response in Gallus gallus domesticus. PLoS ONE 15, e0230021 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Daneshmand, A., Kermanshahi, H., Sekhavati, M. H., Javadmanesh, A. & Ahmadian, M. Antimicrobial peptide, cLF36, affects performance and intestinal morphology, microflora, junctional proteins, and immune cells in broilers challenged with E. coli. Sci. Rep. 9, 14176 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Liu, H. Y. et al. Alternatives to antibiotics in pig production: looking through the lens of immunophysiology. Stress. Biol. 4, 1 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Popitool, K. et al. Potential of Pm11 antimicrobial peptide against bovine mastitis pathogens. Am. J. Vet. Res. 84, ajvr.22.06.0096 (2023).

    Google Scholar 

  126. Orozco, R. M. Q. et al. Employment of mastoparan-like peptides to prevent Staphylococcus aureus associated with bovine mastitis. J. Bacteriol. 206, e0007124 (2024).

    Article  PubMed  Google Scholar 

  127. Yoon, J. H. et al. Effects of dietary supplementation of antimicrobial peptide-A3 on growth performance, nutrient digestibility, intestinal and fecal microflora and intestinal morphology in weanling pigs. Anim. Feed Sci. Technol. 177, 98–107 (2012).

    Article  CAS  Google Scholar 

  128. Craig, M. et al. AI and drug discovery. Cell. Rep. Phys. Sci. 3, 101142 (2022).

    Article  Google Scholar 

  129. Fernandes, F. C. et al. Geometric deep learning as a potential tool for antimicrobial peptide prediction. Front. Bioinform. 3, 1216362 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Cardoso, M. H. et al. Computer-aided design of antimicrobial peptides: are we generating effective drug candidates? Front. Microbiol. 10, 3097 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Cesaro, A. & de la Fuente-Nunez, C. Antibiotic identified by AI. Nat. Chem. Biol. 19, 1296–1298 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Maasch, J. R. M. A., Torres, M. D. T., Melo, M. C. R. & de la Fuente-Nunez, C. Molecular de-extinction of ancient antimicrobial peptides enabled by machine learning. Cell Host Microbe 31, 1260–1274 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Santos-Júnior, C. D. et al. Discovery of antimicrobial peptides in the global microbiome with machine learning. Cell 187, 3761–3778 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Aguilera-Puga, M. D. C. & Plisson, F. Structure-aware machine learning strategies for antimicrobial peptide discovery. Sci. Rep. 14, 11995 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

N.G.O.J., C.M.S. and D.F.B. are supported by FUNDECT. M.H.C. is supported by CNPq and FUNDECT. O.L.F. is supported by CNPq, CAPES and FUNDECT.

Author information

Authors and Affiliations

Authors

Contributions

N.G.O.J., C.M.S., D.F.B. and M.H.C contributed to writing, editing and researching data for the article and contributing to the discussion of this manuscript. M.H.C. and O.L.F. contributed to discussing, reviewing and editing the manuscript before submission.

Corresponding authors

Correspondence to Marlon H. Cardoso or Octávio L. Franco.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Microbiology thanks Marc Devocelle; Man-Wah Tan, who co-reviewed with Craig MacNair; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Oliveira Júnior, N.G., Souza, C.M., Buccini, D.F. et al. Antimicrobial peptides: structure, functions and translational applications. Nat Rev Microbiol 23, 687–700 (2025). https://doi.org/10.1038/s41579-025-01200-y

Download citation

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41579-025-01200-y

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research