{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T11:22:50Z","timestamp":1787570570874,"version":"build-2736575974"},"reference-count":90,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>\n                    The growing threat of antimicrobial resistance has increased the need for anti-infective approaches beyond conventional single-target antibiotics. Defensins, a conserved family of cysteine-rich antimicrobial peptides, are promising candidates owing to their structural stability, membrane activity, target-specific mechanisms, immunomodulatory functions, and potential synergy with existing antibiotics. This critical narrative review discusses defensins as potential therapeutics against antimicrobial-resistant pathogens, with a focus on structure-activity relationships, bacterial envelope biology, resistance evolution and cross-resistance, antibiofilm activity, and translational feasibility. Data were synthesized from mammalian, plant, fungal, and insect defensins, together with defensin-derived peptides and defensin mimetics. Unrelated AMPs were included only as contextual comparators and were not treated as defensin-specific evidence. Antibacterial proof-of-concept and translational-readiness evidence were appraised separately, including activity under physiological ionic-strength and serum conditions, protease stability, cytotoxicity, hemolysis, resistance selection, and\n                    <jats:italic>in vivo<\/jats:italic>\n                    efficacy. However, clinical translation has been hampered by inconsistent testing standards, incomplete pharmacokinetic\/pharmacodynamic characterization, safety concerns, manufacturing challenges, and inadequate resistance surveillance. Existing evidence does not support classifying defensins as resistance-proof or uniformly less resistance-prone than conventional antibiotics. Instead, they should be regarded as versatile scaffolds whose resistance risk requires candidate-specific evaluation. Future studies should combine standardized broth microdilution with testing in serum, protease-rich environments, and mature biofilms. Candidate progression should require infection-site PK\/PD, route-appropriate safety, and efficacy in chronic-wound, device-biofilm, or mucosal-infection models. AI-guided design and delivery systems should advance only when they demonstrably improve stability, exposure, activity, or tolerability, with resistance monitored throughout development and use.\n                  <\/jats:p>","DOI":"10.3389\/fcimb.2026.1881716","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T10:39:51Z","timestamp":1787567991000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Defensins as natural antimicrobial peptide scaffolds against antimicrobial-resistant pathogens: mechanisms, resistance risks, and translational prospects"],"prefix":"10.3389","volume":"16","author":[{"given":"Emad M.","family":"Abdallah","sequence":"first","affiliation":[{"name":"Department of Biology, College of Science, Qassim University","place":["Buraydah, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samiah Hamad","family":"Al-Mijalli","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Sciences, Princess Nourah bint Abdulrahman University","place":["Riyadh, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nawal","family":"Al Hakawati","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, Beirut Arab University","place":["Tripoli, Lebanon"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alissar","family":"Al Khatib","sequence":"additional","affiliation":[{"name":"Department of General Studies, Almoosa College of Health Sciences","place":["Al Ahsaa, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/plants12173077","article-title":"Back to nature: medicinal plants as promising sources for antibacterial drugs in the post-antibiotic era","volume":"12","author":"Abdallah","year":"2023","journal-title":"Plants"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0325722","article-title":"A novel peptide mimetic, brilacidin, for combating multidrug-resistant Neisseria gonorrhoeae","volume":"20","author":"Abdelsattar","year":"2025","journal-title":"PLoS One"},{"key":"B3","doi-asserted-by":"publisher","first-page":"13535","DOI":"10.1039\/D4RA00631C","article-title":"Nanoparticles incorporated hydrogels for delivery of antimicrobial agents: developments and trends","volume":"14","author":"Ahmad","year":"2024","journal-title":"RSC Adv."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.microb.2025.100337","article-title":"The role of antimicrobial peptides in overcoming antibiotic resistance","volume":"7","author":"Ali","year":"2025","journal-title":"Microbe"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25137335","article-title":"The antimicrobial activity of human defensins at physiological non-permeabilizing concentrations is caused by the inhibition of the plasma membrane H+-ATPases","volume":"25","author":"Andr\u00e9s","year":"2024","journal-title":"Int. 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