journal article·2024-10-29Open access

Innovative Strategies and Methodologies in Antimicrobial Peptide Design

Devesh Pratap Verma, Amit Kumar Tripathi, Ashwani Kumar Thakur

Journal of Functional Biomaterials· Volume 15· Issue 11

Abstract

Multiple lines of research have led to the hypothesis that antimicrobial peptides (AMPs) are an important component of the innate immune response, playing a vital role in the defense against a wide range of infectious diseases. In this review, we explore the occurrence and availability of antimicrobial proteins and peptides across various species, highlighting their natural abundance and evolutionary significance. The design of AMPs has been driven by the identification of key structural and functional features, which are essential for optimizing their antimicrobial activity and reducing toxicity to host cells. We discuss various approaches, including rational design, high-throughput screening, and computational modeling, that have been employed to develop novel AMPs with enhanced efficacy. A particular focus is given to the identification and characterization of peptide fragments derived from naturally occurring host defense proteins, which offer a promising avenue for the discovery of new AMPs. The incorporation of artificial intelligence (AI) and machine learning (ML) tools into AMP research has further accelerated the identification, optimization, and application of these peptides. This review also discusses the current status and therapeutic potential of AMPs, emphasizing their role in addressing the growing issue of antibiotic resistance. The conclusion highlights the importance of continued research and innovation in AMP development to fully harness their potential as next-generation antimicrobial agents.
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Research context

OpenAlex topics: Antimicrobial Peptides and Activities · Biochemical and Structural Characterization · vaccines and immunoinformatics approaches

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Biological Sciences & Bioengineering, Indian Institute of Technology, Kanpur 208016, Uttar Pradesh, India

Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA

References (100+)

Show source-provided references
1. Alexander Fleming (1881–1955): Discoverer of penicillin10.11622/smedj.2015105 ↗
2. Muteeb, G., Rehman, M.T., Shahwan, M., and Aatif, M. (2023). Origin of Antibiotics and Antibiotic Resistance, and Their Impacts on Drug Development: A Narrative Review. Pharmaceuticals, 16.10.20944/preprints202306.1921.v1 ↗
3. Origins and evolution of antibiotic resistance10.1128/MMBR.00016-10 ↗
4. Antimicrobial resistance: Prevalence, economic burden, mechanisms of resistance and strategies to overcome10.1016/j.ejps.2021.106103 ↗
5. Min, K.H., Kim, K.H., Ki, M.R., and Pack, S.P. (2024). Antimicrobial Peptides and Their Biomedical Applications: A Review. Antibiotics, 13.10.3390/antibiotics13090794 ↗
6. Bucataru, C., and Ciobanasu, C. (2024). Antimicrobial peptides: Opportunities and challenges in overcoming resistance. Microbiol. Res., 286.10.1016/j.micres.2024.127822 ↗
7. The role of cationic antimicrobial peptides in innate host defences10.1016/S0966-842X(00)01823-0 ↗
8. Antimicrobial Peptides: An Overview of their Structure, Function and Mechanism of Action10.2174/0929866529666220613102145 ↗
9. Interaction between Antimicrobial Peptide Magainin 2 and Nonlipid Components in the Bacterial Outer Envelope10.1021/acs.jpcb.2c02768 ↗
10. PR-39, a syndecan-inducing antimicrobial peptide, binds and affects p130(Cas)10.1074/jbc.273.44.28978 ↗
11. Mazurkiewicz-Pisarek, A., Baran, J., and Ciach, T. (2023). Antimicrobial Peptides: Challenging Journey to the Pharmaceutical, Biomedical, and Cosmeceutical Use. Int. J. Mol. Sci., 24.10.3390/ijms24109031 ↗
12. Dini, I., De Biasi, M.G., and Mancusi, A. (2022). An Overview of the Potentialities of Antimicrobial Peptides Derived from Natural Sources. Antibiotics, 11.10.3390/antibiotics11111483 ↗
13. Bakare, O.O., Gokul, A., Fadaka, A.O., Wu, R., Niekerk, L.A., Barker, A.M., Keyster, M., and Klein, A. (2022). Plant Antimicrobial Peptides (PAMPs): Features, Applications, Production, Expression, and Challenges. Molecules, 27.10.3390/molecules27123703 ↗
14. Huan, Y., Kong, Q., Mou, H., and Yi, H. (2020). Antimicrobial Peptides: Classification, Design, Application and Research Progress in Multiple Fields. Front. Microbiol., 11.10.3389/fmicb.2020.582779 ↗
15. Bin Hafeez, A., Jiang, X., Bergen, P.J., and Zhu, Y. (2021). Antimicrobial Peptides: An Update on Classifications and Databases. Int. J. Mol. Sci., 22.10.3390/ijms222111691 ↗
16. Antimicrobial peptides in reptiles10.3390/ph7060723 ↗
17. For how long should carotid endarterectomy surveillance be continued?
18. Nguyen, T.T.T., Allan, B., Wheler, C., Koster, W., Gerdts, V., and Dar, A. (2021). Avian antimicrobial peptides: In vitro and in ovo characterization and protection from early chick mortality caused by yolk sac infection. Sci. Rep., 11.10.1038/s41598-021-81734-2 ↗
19. Antimicrobial peptides from marine invertebrates10.1128/AAC.48.10.3645-3654.2004 ↗
20. Antimicrobial peptides as natural bio-preservative to enhance the shelf-life of food10.1007/s13197-016-2318-5 ↗
21. Lacticin 3147, a broad-spectrum bacteriocin which selectively dissipates the membrane potential10.1128/AEM.64.2.439-445.1998 ↗
22. The antimicrobial peptides and their potential clinical applications
23. Cardoso, M.H., Orozco, R.Q., Rezende, S.B., Rodrigues, G., Oshiro, K.G.N., Candido, E.S., and Franco, O.L. (2019). Computer-Aided Design of Antimicrobial Peptides: Are We Generating Effective Drug Candidates?. Front. Microbiol., 10.10.3389/fmicb.2019.03097 ↗
24. Fernandez de Ullivarri, M., Arbulu, S., Garcia-Gutierrez, E., and Cotter, P.D. (2020). Antifungal Peptides as Therapeutic Agents. Front. Cell. Infect. Microbiol., 10.10.3389/fcimb.2020.00105 ↗
25. Yan, J., Cai, J., Zhang, B., Wang, Y., Wong, D.F., and Siu, S.W.I. (2022). Recent Progress in the Discovery and Design of Antimicrobial Peptides Using Traditional Machine Learning and Deep Learning. Antibiotics, 11.10.3390/antibiotics11101451 ↗
26. Milk-Derived Antimicrobial Peptides: Overview, Applications, and Future Perspectives10.1007/s12602-022-10004-y ↗
27. Saebo, I.P., Bjoras, M., Franzyk, H., Helgesen, E., and Booth, J.A. (2023). Optimization of the Hemolysis Assay for the Assessment of Cytotoxicity. Int. J. Mol. Sci., 24.10.3390/ijms24032914 ↗
28. Mechanism of action of antimicrobial peptide P5 truncations against Pseudomonas aeruginosa and Staphylococcus aureus10.1186/s13568-019-0843-0 ↗
29. Mechanism and kinetics of pore formation in membranes by water-soluble amphipathic peptides10.1073/pnas.0710625105 ↗
30. Mode of action of membrane active antimicrobial peptides10.1002/bip.10260 ↗
31. Barrel-stave model or toroidal model? A case study on melittin pores10.1016/S0006-3495(01)75802-X ↗
32. Slezina, M.P., Istomina, E.A., Korostyleva, T.V., and Odintsova, T.I. (2022). The gamma-Core Motif Peptides of Plant AMPs as Novel Antimicrobials for Medicine and Agriculture. Int. J. Mol. Sci., 24.10.3390/ijms24010483 ↗
33. HIV-1 Nef CAWLEAQ motif: A regulator of monocytes invasion through ENO1 modulation10.1007/s11010-018-3300-5 ↗
34. Tripathi, A.K., Kumari, T., Harioudh, M.K., Yadav, P.K., Kathuria, M., Shukla, P.K., Mitra, K., and Ghosh, J.K. (2017). Identification of GXXXXG motif in Chrysophsin-1 and its implication in the design of analogs with cell-selective antimicrobial and anti-endotoxin activities. Sci. Rep., 7.10.1038/s41598-017-03576-1 ↗
35. Single Amino Acid Substitutions at Specific Positions of the Heptad Repeat Sequence of Piscidin-1 Yielded Novel Analogs That Show Low Cytotoxicity and In Vitro and In Vivo Antiendotoxin Activity10.1128/AAC.02341-15 ↗
36. Selective phenylalanine to proline substitution for improved antimicrobial and anticancer activities of peptides designed on phenylalanine heptad repeat10.1016/j.actbio.2017.05.007 ↗
37. Modulation of anti-endotoxin property of Temporin L by minor amino acid substitution in identified phenylalanine zipper sequence10.1042/BCJ20160713 ↗
38. Karnati, P., Gonuguntala, R., Barbadikar, K.M., Mishra, D., Jha, G., Prakasham, V., Chilumula, P., Shaik, H., Pesari, M., and Sundaram, R.M. (2022). Performance of Novel Antimicrobial Protein Bg_9562 and In Silico Predictions on Its Properties with Reference to Its Antimicrobial Efficiency against Rhizoctonia solani. Antibiotics, 11.10.3390/antibiotics11030363 ↗
39. Chemical modifications to increase the therapeutic potential of antimicrobial peptides10.1016/j.peptides.2021.170666 ↗
40. Tiwari, A., Gomez-Alvarez, V., Siponen, S., Sarekoski, A., Hokajärvi, A.-M., Kauppinen, A., Torvinen, E., Miettinen, I.T., and Pitkänen, T. (2022). Bacterial Genes Encoding Resistance Against Antibiotics and Metals in Well-Maintained Drinking Water Distribution Systems in Finland. Front. Microbiol., 12.10.3389/fmicb.2021.803094 ↗
41. Kumar, P., Kizhakkedathu, J.N., and Straus, S.K. (2018). Antimicrobial Peptides: Diversity, Mechanism of Action and Strategies to Improve the Activity and Biocompatibility In Vivo. Biomolecules, 8.10.3390/biom8010004 ↗
42. Tripathi, A.K., Singh, J., Trivedi, R., and Ranade, P. (2023). Shaping the Future of Antimicrobial Therapy: Harnessing the Power of Antimicrobial Peptides in Biomedical Applications. J. Funct. Biomater., 14.10.20944/preprints202309.1916.v1 ↗
43. Bobde, S.S., Alsaab, F.M., Wang, G., and Van Hoek, M.L. (2021). Ab initio Designed Antimicrobial Peptides Against Gram-Negative Bacteria. Front. Microbiol., 12.10.3389/fmicb.2021.715246 ↗
44. Role of peptide hydrophobicity in the mechanism of action of alpha-helical antimicrobial peptides10.1128/AAC.00925-06 ↗
45. Antimicrobial peptides10.3390/ph6121543 ↗
46. 10-Residue MyD88-Peptide Adopts beta-Sheet Structure, Self-Assembles, Binds to Lipopolysaccharides, and Rescues Mice from Endotoxin-Mediated Lung-Infection and Death10.1021/acschembio.2c00569 ↗
47. Characterization of a Myeloid Differentiation Factor 2-Derived Peptide that Facilitates THP-1 Macrophage-Mediated Phagocytosis of Gram-Negative Bacteria10.1021/acsinfecdis.3c00274 ↗
48. An MD2-derived peptide promotes LPS aggregation, facilitates its internalization in THP-1 cells, and inhibits LPS-induced pro-inflammatory responses10.1007/s00018-017-2735-2 ↗
49. Tripathi, A.K., Desai, P.P., Tyagi, A., Lampe, J.B., Srivastava, Y., Donkor, M., Jones, H.P., Dzyuba, S.V., Crossley, E., and Williams, N.S. (2024). Short peptides based on the conserved regions of MIEN1 protein exhibit anticancer activity by targeting the MIEN1 signaling pathway. J. Biol. Chem., 300.10.1016/j.jbc.2024.105680 ↗
50. Guo, C., Trivedi, R., Tripathi, A.K., Nandy, R.R., Wagner, D.C., Narra, K., and Chaudhary, P. (2022). Higher Expression of Annexin A2 in Metastatic Bladder Urothelial Carcinoma Promotes Migration and Invasion. Cancers, 14.10.3390/cancers14225664 ↗
51. Abstract 2184: Short Peptides derived from MIEN1 and their analogs exhibit anti-cancer activity in breast and prostate cancer cells10.1158/1538-7445.AM2023-2184 ↗
52. Hassan, M.F., Qutb, A.M., and Dong, W. (2021). Prediction and Activity of a Cationic alpha-Helix Antimicrobial Peptide ZM-804 from Maize. Int. J. Mol. Sci., 22.10.3390/ijms22052643 ↗
53. Design of imperfectly amphipathic alpha-helical antimicrobial peptides with enhanced cell selectivity10.1016/j.actbio.2013.08.043 ↗
54. Antimicrobial activity of cathelicidins BMAP28, SMAP28, SMAP29, and PMAP23 against Pasteurella multocida is more broad-spectrum than host species specific10.1016/j.vetmic.2006.08.005 ↗
55. WLBU2 Antimicrobial Peptide as a Potential Therapeutic for Treatment of Resistant Bacterial10.4274/tjps.galenos.2020.43078 ↗
56. APD3: The antimicrobial peptide database as a tool for research and education10.1093/nar/gkv1278 ↗
57. CAMP: Collection of sequences and structures of antimicrobial peptides10.1093/nar/gkt1157 ↗
58. DADP: The database of anuran defense peptides10.1093/bioinformatics/bts141 ↗
59. The amphipathic design in helical antimicrobial peptides10.1002/cmdc.202300480 ↗
60. Kang, H.K., Choi, M.C., Seo, C.H., and Park, Y. (2018). Therapeutic Properties and Biological Benefits of Marine-Derived Anticancer Peptides. Int. J. Mol. Sci., 19.10.3390/ijms19030919 ↗
61. DBAASP v3: Database of antimicrobial/cytotoxic activity and structure of peptides as a resource for development of new therapeutics10.1093/nar/gkaa991 ↗
62. Deep-AmPEP30: Improve Short Antimicrobial Peptides Prediction with Deep Learning10.1016/j.omtn.2020.05.006 ↗
63. Dee, W. (2022). LMPred: Predicting antimicrobial peptides using pre-trained language models and deep learning. Bioinform. Adv., 2.10.1093/bioadv/vbac021 ↗
64. Yue, L., Song, L., Zhu, S., Fu, X., Li, X., He, C., and Li, J. (2024). Machine learning assisted rational design of antimicrobial peptides based on human endogenous proteins and their applications for cosmetic preservative system optimization. Sci. Rep., 14.10.1038/s41598-023-50832-8 ↗
65. Artificial intelligence in drug discovery and development10.1016/j.drudis.2020.10.010 ↗
66. Muratspahic, E., Retzl, B., Duerrauer, L., Freissmuth, M., Becker, C.F.W., and Gruber, C.W. (2021). Genome Mining-Based Discovery of Blenny Fish-Derived Peptides Targeting the Mouse kappa-Opioid Receptor. Front. Pharmacol., 12.10.3389/fphar.2021.773029 ↗
67. Genome mining for lasso peptides: Past, present, and future10.1007/s10295-019-02197-z ↗
68. Challenges and advances in genome mining of ribosomally synthesized and post-translationally modified peptides (RiPPs)10.1016/j.synbio.2020.06.002 ↗
69. Mining the bacterial genome to discover new antimicrobial molecules10.15252/emmm.202115409 ↗
70. Development strategies and application of antimicrobial peptides as future alternatives to in-feed antibiotics10.1016/j.scitotenv.2024.172150 ↗
71. Effect of N-terminal acetylation on lytic activity and lipid-packing perturbation induced in model membranes by a mastoparan-like peptide10.1016/j.bbamem.2017.12.018 ↗
72. Effect of Amino Acid Substitutions on Biological Activity of Antimicrobial Peptide: Design, Recombinant Production, and Biological Activity
73. Kang, S.J., Nam, S.H., and Lee, B.J. (2022). Engineering Approaches for the Development of Antimicrobial Peptide-Based Antibiotics. Antibiotics, 11.10.3390/antibiotics11101338 ↗
74. Spermine-Conjugated Short Proline-Rich Lipopeptides as Broad-Spectrum Intracellular Targeting Antibacterial Agents10.1021/acs.jmedchem.1c01809 ↗
75. Bellavita, R., Braccia, S., Galdiero, S., and Falanga, A. (2023). Glycosylation and Lipidation Strategies: Approaches for Improving Antimicrobial Peptide Efficacy. Pharmaceuticals, 16.10.3390/ph16030439 ↗
76. Tandem Repeat of a Short Human Chemerin-Derived Peptide and Its Nontoxic d-Lysine-Containing Enantiomer Display Broad-Spectrum Antimicrobial and Antitubercular Activities10.1021/acs.jmedchem.1c01352 ↗
77. Nukacin ISK-1, a bacteriostatic lantibiotic10.1128/AAC.01623-08 ↗
78. The Vast Structural Diversity of Antimicrobial Peptides10.1016/j.tips.2019.04.012 ↗
79. The Disulfide Bond of the Peptide Thanatin Is Dispensible for Its Antimicrobial Activity In Vivo and In Vitro10.1128/AAC.00041-16 ↗
80. Engineering disulfide bridges to dissect antimicrobial and chemotactic activities of human beta-defensin 310.1073/pnas.1533186100 ↗
81. Hydrogelation Through Self-Assembly of Fmoc-Peptide Functionalized Cationic Amphiphiles: Potent Antibacterial Agent10.1021/jp909520w ↗
82. Development of mechanism-based antibacterial synergy between Fmoc-phenylalanine hydrogel and aztreonam10.1039/C9BM01978B ↗
83. Rings in Clinical Trials and Drugs: Present and Future10.1021/acs.jmedchem.2c00473 ↗
84. The effect of halogenation on the antimicrobial activity, antibiofilm activity, cytotoxicity and proteolytic stability of the antimicrobial peptide Jelleine-I10.1016/j.peptides.2018.11.006 ↗
85. Halogen-pi Interactions in the Cytochrome P450 Active Site: Structural Insights into Human CYP2B6 Substrate Selectivity10.1021/acschembio.7b00056 ↗
86. Systematic discovery of multicomponent therapeutics10.1073/pnas.1337088100 ↗
87. Lyu, Y., Yang, Y., Lyu, X., Dong, N., and Shan, A. (2016). Antimicrobial activity, improved cell selectivity and mode of action of short PMAP-36-derived peptides against bacteria and Candida. Sci. Rep., 6.10.1038/srep27258 ↗
88. Taheri-Araghi, S. (2024). Synergistic action of antimicrobial peptides and antibiotics: Current understanding and future directions. Front. Microbiol., 15.10.3389/fmicb.2024.1390765 ↗
89. Rima, M., Rima, M., Fajloun, Z., Sabatier, J.M., Bechinger, B., and Naas, T. (2021). Antimicrobial Peptides: A Potent Alternative to Antibiotics. Antibiotics, 10.10.3390/antibiotics10091095 ↗
90. Liquid chromatography-tandem mass spectrometry based method development and validation of S016-1271 (LR8P), a novel cationic antimicrobial peptide for its application to pharmacokinetic studies10.1016/j.jpba.2019.01.046 ↗
91. Arifian, H., Maharani, R., Megantara, S., Gazzali, A.M., and Muchtaridi, M. (2022). Amino-Acid-Conjugated Natural Compounds: Aims, Designs and Results. Molecules, 27.10.3390/molecules27217631 ↗
92. Tripathi, A.K., and Vishwanatha, J.K. (2022). Role of Anti-Cancer Peptides as Immunomodulatory Agents: Potential and Design Strategy. Pharmaceutics, 14.10.3390/pharmaceutics14122686 ↗
93. Huang, H.W. (2020). DAPTOMYCIN, its membrane-active mechanism vs. that of other antimicrobial peptides. Biochim. Biophys. Acta Biomembr., 1862.10.1016/j.bbamem.2020.183395 ↗
94. Safety and Efficacy of Human Chorionic Gonadotropin Hormone-Derivative EA-230 in Cardiac Surgery Patients: A Randomized Double-Blind Placebo-Controlled Study10.1097/CCM.0000000000004847 ↗
95. Colistin and polymyxin B: A re-emergence10.4103/0972-5229.56048 ↗
96. Li, X., Zuo, S., Wang, B., Zhang, K., and Wang, Y. (2022). Antimicrobial Mechanisms and Clinical Application Prospects of Antimicrobial Peptides. Molecules, 27.10.3390/molecules27092675 ↗
97. A randomized double-blind trial of iseganan in prevention of ventilator-associated pneumonia10.1164/rccm.200504-656OC ↗
98. A two-part phase 1 study to establish and compare the safety and local tolerability of two nasal formulations of XF-73 for decolonisation of Staphylococcus aureus: A previously investigated 0.5mg/g viscosified gel formulation versus a modified formulation10.1016/j.jgar.2019.09.017 ↗
99. Clinical and microbial evaluation of a histatin-containing mouthrinse in humans with experimental gingivitis: A phase-2 multi-center study10.1034/j.1600-051x.2002.290212.x ↗
100. Pharmacodynamic Effects of Topical Omiganan in Patients With Mild to Moderate Atopic Dermatitis in a Randomized, Placebo-Controlled, Phase II Trial10.1111/cts.12792 ↗