{"doi":"10.3390/molecules31122186","title":"Covalent Inhibitors in Antimicrobial Drug Development—Beyond β-Lactams","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 β-lactam, the reactive warhead that forms the covalent adduct, exemplified by later-generation cephalosporins with approvals into 2020. In parallel, early non-β-lactam covalent agents also emerged, extending covalent mechanisms beyond β-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-β-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>","journal":"Molecules","year":2026,"id":612448,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1045636,"name":"Dustin Duncan","orcid":"0000-0003-1240-8495","position":1,"is_corresponding":false},{"id":1576908,"name":"Ghazaleh Jafari","orcid":"0009-0009-0082-8995","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Covalent Inhibitors in Antimicrobial Drug Development—Beyond β-Lactams","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 β-lactam, the reactive warhead that forms the covalent adduct, exemplified by later-generation cephalosporins with approvals into 2020. In parallel, early non-β-lactam covalent agents also emerged, extending covalent mechanisms beyond β-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-β-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>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"42357581","pmcid":null,"openalex_id":"https://openalex.org/W7165635239","authors":[],"funders":[{"funder_name":"Natural Sciences and Engineering Research Council of Canada","grant_id":"RGPIN-2025-04514","title":null}],"total_grants":1,"fwci":0.0,"citation_percentile":0.67157116,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.mdpi.com/1420-3049/31/12/2186/pdf?version=1782122553","host_type":"journal"},{"url":"https://www.mdpi.com/1420-3049/31/12/2186/pdf?version=1782122553","host_type":"publisher"},{"url":"https://www.mdpi.com/1420-3049/31/12/2186/pdf","host_type":"publisher"},{"url":"https://doi.org/10.3390/molecules31122186","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/42357581","host_type":"repository"},{"url":"https://doaj.org/article/57abdfbab55246b29c5c6664ed1123a1","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13304705/","host_type":"repository"}],"fields_of_study":["Synthesis of β-Lactam Compounds","Antibiotics Pharmacokinetics and Efficacy","Antimicrobial agents and applications","Humans","beta-Lactams","Drug Development","Anti-Infective Agents","Drug Design","beta Lactam Antibiotics","Animals","Anti-Bacterial Agents"],"mesh_terms":["Drug Development","beta Lactam Antibiotics","Animals","Anti-Infective Agents","Anti-Bacterial Agents","Humans","Drug Design","beta-Lactams"],"keywords":["Covalent bond","Antimicrobial","Warhead","Penicillin","Antibiotics","Antimicrobial drug","Antibacterial","Antiviral","drug discovery","antifungal","Drug Development","Antiparasitic","Chemical Biology","Covalent Inhibitor"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-02T03:29:01.820304Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}