{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:09:41Z","timestamp":1791850181465,"version":"4.3.4"},"reference-count":260,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Puerto Rico IDeA Networks of Biomedical Research Excellence (PRINBRE) program","award":["P20-GM103475"],"award-info":[{"award-number":["P20-GM103475"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Antimicrobial resistance (AMR) poses an escalating global health crisis driven by multidrug-resistant ESKAPE pathogens and emerging fungal threats such as Candida auris (C. auris). In response to this urgent need for new therapeutic strategies, antimicrobial peptides (AMPs) represent a mechanistically distinct alternative to conventional antibiotics due to their membrane-targeting mechanisms and a reduced propensity for resistance development; however, clinical translation has been hindered by toxicity, instability and manufacturing constraints. Recent advances in artificial intelligence (AI) are reshaping AMP discovery and optimization. Machine learning (ML), deep learning (DL) and transformer-based protein language models now enable improved prediction of antimicrobial activity, selectivity, protease stability and host toxicity. Generative approaches, including variational autoencoders, diffusion models and reinforcement learning, facilitate de novo multi-objective peptide design and pathogen-directed optimization against resistant bacteria and multidrug-resistant fungal pathogens. Integrated design\u2013test\u2013learn pipelines are accelerating iterative peptide engineering by tightly coupling computational prediction with experimental validation. Clinically used peptide-derived antibiotics such as polymyxins and daptomycin demonstrate the therapeutic feasibility of peptide-based antimicrobials, while investigational peptides, including pexiganan, illustrate ongoing translational progress. Although no fully AI-designed AMP has yet achieved regulatory approval, the accelerating convergence of computational modeling and experimental validation suggests a rapidly evolving translational landscape. Advancing scalable, surveillance-informed AI frameworks that integrate resistance data, predictive safety modeling and delivery optimization will be essential to accelerate the clinical translation of next-generation, multi-objective AMPs against high-risk resistant pathogens.<\/jats:p>","DOI":"10.3390\/microorganisms14030591","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T11:05:44Z","timestamp":1772795144000},"page":"591","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Artificial Intelligence-Driven Discovery and Optimization of Antimicrobial Peptides Targeting ESKAPE Pathogens and Multidrug-Resistant Fungi"],"prefix":"10.3390","volume":"14","author":[{"given":"Calina","family":"Wu-Mo","sequence":"first","affiliation":[{"name":"Department of Biology, University of Puerto Rico, Cayey Campus, Cayey 00737, Puerto Rico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariana","family":"Flores-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Puerto Rico, Cayey Campus, Cayey 00737, Puerto Rico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jezrael","family":"Mel\u00e9ndez-Delgado","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Puerto Rico, Cayey Campus, Cayey 00737, Puerto Rico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Ortiz-G\u00f3mez","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Sciences & Technology, Ana G. M\u00e9ndez University, Gurabo Campus, Gurabo 00777, Puerto Rico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9ctor","family":"Mel\u00e9ndez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Ponce Health Science University, Ponce 00716, Puerto Rico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1162-1614","authenticated-orcid":false,"given":"Rafael","family":"Maldonado-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Puerto Rico, Cayey Campus, Cayey 00737, Puerto Rico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/S0140-6736(21)02724-0","article-title":"Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis","volume":"399","author":"Murray","year":"2022","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1038\/s41579-024-01054-w","article-title":"ESKAPE pathogens: Antimicrobial resistance, epidemiology, clinical impact and therapeutics","volume":"22","author":"Miller","year":"2024","journal-title":"Nat. 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