{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:15:30Z","timestamp":1790190930194,"version":"4.1.0"},"reference-count":184,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Brock Start-up Funds"},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2025-04514"],"award-info":[{"award-number":["RGPIN-2025-04514"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RGPIN-2025-04514"],"award-info":[{"award-number":["RGPIN-2025-04514"]}],"id":[{"id":"https:\/\/ror.org\/01h531d29","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>For nearly a century, since the discovery of penicillin by Alexander Fleming, we have used covalent inhibitors as antimicrobial drugs. The success of penicillin in treating microbial infections led to numerous other antibiotics containing \u03b2-lactam, the reactive warhead that forms the covalent adduct, exemplified by later-generation cephalosporins with approvals into 2020. In parallel, early non-\u03b2-lactam covalent agents also emerged, extending covalent mechanisms beyond \u03b2-lactam antibacterials to antifungal, antiparasitic, and antiviral applications. Despite the successes of covalent mechanisms of action, there are still considerable safety concerns due to the possibility of off-target covalent adducts which may lead to significant side effects. This review provides an overview of non-\u03b2-lactam covalent antimicrobials across all major pathogen classes, organized by their warhead class, covalency, and resistance mechanisms, and outlines design and clinical-level mitigation strategies. We trace the field from the serendipitous discovery of penicillin to the intentional design of new drugs, with a discussion of changes in perception and evolution of technology that enable modern covalent drug design.<\/jats:p>","DOI":"10.3390\/molecules31122186","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T08:19:52Z","timestamp":1782202792000},"page":"2186","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Covalent Inhibitors in Antimicrobial Drug Development\u2014Beyond \u03b2-Lactams"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0082-8995","authenticated-orcid":false,"given":"Ghazaleh","family":"Jafari","sequence":"first","affiliation":[{"name":"Department of Chemistry, Brock University, St. Catharines, ON L2S 3A1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1240-8495","authenticated-orcid":false,"given":"Dustin","family":"Duncan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Brock University, St. Catharines, ON L2S 3A1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"ref_1","first-page":"780","article-title":"On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae. 1929","volume":"79","author":"Fleming","year":"2001","journal-title":"Bull. 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