{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:08:35Z","timestamp":1789135715860,"version":"build-2803163510"},"reference-count":37,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI167977"],"award-info":[{"award-number":["R01AI167977"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI176523"],"award-info":[{"award-number":["R01AI176523"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005302","name":"University of Illinois at Urbana-Champaign","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005302","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In an effort to develop efficacious antibacterials that engage targets for which there is no preexisting resistance, inhibition of the enoyl-acyl carrier protein reductase FabI has shown promise, with triclosan and fabimycin as representative members of the two major drug classes that show activity against important bacterial pathogens. Here, we use a morbidostat and whole-genome sequencing approach to comprehensively evaluate the resistance profiles that arise in pathogenic bacteria in response to these FabI inhibitors. When assessed against E. coli, fabimycin and triclosan were found to induce primarily nonoverlapping resistance profiles, leading to minimal cross-resistance between the two compounds. Furthermore, in vivo evaluation of the prominent resistant mutants indicates poor fitness, with the fittest mutant still susceptible to fabimycin. Collectively, these results suggest the combination use of two antibiotics that engage different positions on the same target as a means to kill pathogenic bacteria and limit resistance.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00339","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T17:17:52Z","timestamp":1788196672000},"page":"3159-3168","source":"Crossref","is-referenced-by-count":0,"title":["Fatty Acid Biosynthesis\nInhibitors\u2500Fabimycin\nand Triclosan\u2500Trigger Distinct Resistance Mutations in FabI\nand Potently Kill Gram-Negative Pathogens"],"prefix":"10.1021","volume":"12","author":[{"given":"Brett N.","family":"Cain","sequence":"first","affiliation":[{"name":"University of Illinois at Urbana\u2212champaign , , , ,","place":["Urbana, Illinois, United States, 61801"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"Kent","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute , , ,","place":["La Jolla, California, United States, 920376"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marinela","family":"Elane","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute , , ,","place":["La Jolla, California, United States, 920376"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Williams","sequence":"additional","affiliation":[{"name":"Walter Reed Army Institute of Research , , ,","place":["Silver Spring, Maryland, United States, 20910"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myung Ryul","family":"Lee","sequence":"additional","affiliation":[{"name":"University of Illinois at Urbana\u2212champaign , , , ,","place":["Urbana, Illinois, United States, 61801"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7962-3950","authenticated-orcid":true,"given":"Gee W.","family":"Lau","sequence":"additional","affiliation":[{"name":"University of Illinois at Urbana\u2212Champaign , , , ,","place":["Urbana, Illinois, United States, 61801"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Hergenrother","sequence":"additional","affiliation":[{"name":"University of Illinois at Urbana\u2212champaign , , , ,","place":["Urbana, Illinois, United States, 61801"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3810-9824","authenticated-orcid":true,"given":"Andrei L.","family":"Osterman","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute , , ,","place":["La Jolla, California, United States, 920376"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"issue":"2","key":"2026091109082372000_cit1","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1093\/jac\/dkz401","article-title":"Pandrug-resistant Gram-negative bacteria:\na systematic review of current epidemiology, prognosis and treatment\noptions","volume":"75","author":"Karakonstantis","year":"2019","journal-title":"J. Antimicrob. Chemother."},{"issue":"10459","key":"2026091109082372000_cit2","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1016\/S0140-6736(24)01867-1","article-title":"Global\nburden of bacterial antimicrobial resistance 1990\u20132021: a systematic\nanalysis with forecasts to 2050","volume":"404","author":"Naghavi","year":"2024","journal-title":"The Lancet"},{"issue":"3","key":"2026091109082372000_cit3","doi-asserted-by":"publisher","first-page":"a027045","DOI":"10.1101\/cshperspect.a027045","article-title":"Resistance Mechanisms\nand the Future of Bacterial Enoyl-Acyl\nCarrier Protein Reductase (FabI) Antibiotics","volume":"6","author":"Yao","year":"2016","journal-title":"Cold Spring Harbor Perspect. Med."},{"key":"2026091109082372000_cit4","doi-asserted-by":"publisher","first-page":"112757","DOI":"10.1016\/j.ejmech.2020.112757","article-title":"FabI (enoyl acyl carrier\nprotein reductase) - A potential\nbroad spectrum therapeutic target and its inhibitors","volume":"208","author":"Rana","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"2026091109082372000_cit5","volume-title":"Halogenated hydroxy-diphenyl\nethers","author":"Model","year":"1966"},{"issue":"1","key":"2026091109082372000_cit6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1574-6968.2001.tb10772.x","article-title":"Triclosan:\na widely used biocide and its link to antibiotics","volume":"202","author":"Schweizer","year":"2001","journal-title":"FEMS Microbiol Lett."},{"issue":"6693","key":"2026091109082372000_cit7","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1038\/28970","article-title":"Triclosan targets lipid synthesis","volume":"394","author":"McMurry","year":"1998","journal-title":"Nature"},{"issue":"10","key":"2026091109082372000_cit8","doi-asserted-by":"publisher","first-page":"4692","DOI":"10.1128\/AAC.01248-10","article-title":"The MUT056399\ninhibitor of FabI is a new antistaphylococcal compound","volume":"55","author":"Escaich","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"issue":"22","key":"2026091109082372000_cit9","doi-asserted-by":"publisher","first-page":"9914","DOI":"10.1021\/jm301113w","article-title":"From triclosan\ntoward the clinic: discovery of nonbiocidal,\npotent FabI inhibitors for the treatment of resistant bacteria","volume":"55","author":"Gerusz","year":"2012","journal-title":"J. Med. Chem."},{"issue":"10","key":"2026091109082372000_cit10","doi-asserted-by":"publisher","first-page":"3118","DOI":"10.1128\/AAC.46.10.3118-3124.2002","article-title":"Discovery of a novel\nand potent class of FabI-directed antibacterial agents","volume":"46","author":"Payne","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"issue":"11","key":"2026091109082372000_cit11","doi-asserted-by":"publisher","first-page":"5865","DOI":"10.1128\/AAC.01411-12","article-title":"Mode of action,\nin vitro activity,\nand in vivo efficacy of AFN-1252, a selective antistaphylococcal FabI\ninhibitor","volume":"56","author":"Kaplan","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"issue":"3","key":"2026091109082372000_cit12","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.1128\/AAC.01741-15","article-title":"Efficacy and Safety of AFN-1252,\nthe First Staphylococcus-Specific Antibacterial Agent, in the Treatment\nof Acute Bacterial Skin and Skin Structure Infections, Including Those\nin Patients with Significant Comorbidities","volume":"60","author":"Hafkin","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"issue":"10","key":"2026091109082372000_cit13","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00250-20","article-title":"Afabicin, a First-in-Class\nAntistaphylococcal Antibiotic, in the Treatment of Acute Bacterial\nSkin and Skin Structure Infections: Clinical Noninferiority to Vancomycin\/Linezolid","volume":"64","author":"Wittke","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"issue":"1","key":"2026091109082372000_cit14","doi-asserted-by":"publisher","first-page":"8309","DOI":"10.1038\/s41467-025-63508-w","article-title":"The bactericidal\nFabI inhibitor Debio 1453 clears antibiotic-resistant Neisseria gonorrhoeae\ninfection in vivo","volume":"16","author":"Gerusz","year":"2025","journal-title":"Nat. Commun."},{"issue":"8","key":"2026091109082372000_cit15","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1021\/acscentsci.2c00598","article-title":"An Iterative\nApproach Guides Discovery of the FabI Inhibitor Fabimycin, a Late-Stage\nAntibiotic Candidate with In Vivo Efficacy against Drug-Resistant\nGram-Negative Infections","volume":"8","author":"Parker","year":"2022","journal-title":"ACS Cent. Sci."},{"issue":"1","key":"2026091109082372000_cit16","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/s41564-019-0604-5","article-title":"Implementation of permeation rules\nleads to a FabI inhibitor with activity against Gram-negative pathogens","volume":"5","author":"Parker","year":"2020","journal-title":"Nat. Microbiol."},{"issue":"1","key":"2026091109082372000_cit17","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1038\/s41467-018-03447-x","article-title":"Mutual potentiation\ndrives synergy\nbetween trimethoprim and sulfamethoxazole","volume":"9","author":"Minato","year":"2018","journal-title":"Nat.\nCommun."},{"issue":"4","key":"2026091109082372000_cit18","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1111\/j.1365-2885.1994.tb00251.x","article-title":"The sulfonamide-diaminopyrimidine story","volume":"17","author":"van Miert","year":"1994","journal-title":"J. Vet Pharmacol Ther."},{"issue":"suppl 1","key":"2026091109082372000_cit19","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/jac\/39.suppl_1.15","article-title":"In-vitro\nand in-vivo antibacterial activity of quinupristin\/dalfopristin","volume":"39","author":"Bouanchaud","year":"1997","journal-title":"J. Antimicrob. Chemother."},{"issue":"5","key":"2026091109082372000_cit20","doi-asserted-by":"publisher","DOI":"10.1099\/mgen.0.000553","article-title":"Experimental evolution\nin morbidostat reveals converging\ngenomic trajectories on the path to triclosan resistance","volume":"7","author":"Leyn","year":"2021","journal-title":"Microb. Genom."},{"issue":"3","key":"2026091109082372000_cit21","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1038\/nprot.nprot.2013.021","article-title":"Building a\nmorbidostat: an automated\ncontinuous-culture device for studying bacterial drug resistance under\ndynamically sustained drug inhibition","volume":"8","author":"Toprak","year":"2013","journal-title":"Nat.\nProtoc."},{"issue":"1","key":"2026091109082372000_cit22","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/s44259-024-00021-y","article-title":"Two classes of DNA gyrase inhibitors\nelicit distinct\nevolutionary trajectories toward resistance in gram-negative pathogens","volume":"2","author":"Leyn","year":"2024","journal-title":"Npj Antimicrob. Resist."},{"issue":"3","key":"2026091109082372000_cit23","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00987-21","article-title":"Shared and Unique Evolutionary Trajectories\nto Ciprofloxacin\nResistance in Gram-Negative Bacterial Pathogens","volume":"12","author":"Zlamal","year":"2021","journal-title":"mBio"},{"issue":"7995","key":"2026091109082372000_cit24","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1038\/s41586-023-06873-0","article-title":"A novel antibiotic class targeting the lipopolysaccharide\ntransporter","volume":"625","author":"Zampaloni","year":"2024","journal-title":"Nature"},{"issue":"1","key":"2026091109082372000_cit25","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/nrd2202","article-title":"Multi-targeting\nby monotherapeutic antibacterials","volume":"6","author":"Silver","year":"2007","journal-title":"Nat. Rev.\nDrug Discovery"},{"issue":"7","key":"2026091109082372000_cit26","doi-asserted-by":"publisher","first-page":"4264","DOI":"10.1128\/AAC.00535-16","article-title":"A Pathogen-Selective Antibiotic Minimizes Disturbance\nto the Microbiome","volume":"60","author":"Yao","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"issue":"2","key":"2026091109082372000_cit27","first-page":"64","article-title":"Toxicology of 2, 4, 4\u2019-trichloro-2\u2019-hydroxy-diphenyl\nether","volume":"38","author":"Lyman","year":"1969","journal-title":"IMS Ind. Med. Surg."},{"key":"2026091109082372000_cit28","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00809-25","article-title":"Mutations in two-component signaling\nsystems drive experimental evolution of tigecycline and colistin resistance\nin Acinetobacter baumannii","volume":"69","author":"Kent","year":"2025","journal-title":"Antimicrob. Agents\nChemother."},{"issue":"14","key":"2026091109082372000_cit29","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler\ntransform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"issue":"22","key":"2026091109082372000_cit30","doi-asserted-by":"publisher","first-page":"11189","DOI":"10.1093\/nar\/gks918","article-title":"LoFreq: a\nsequence-quality aware, ultra-sensitive variant\ncaller for uncovering cell-population heterogeneity from high-throughput\nsequencing datasets","volume":"40","author":"Wilm","year":"2012","journal-title":"Nucleic Acids Res."},{"issue":"5","key":"2026091109082372000_cit31","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1038\/ng.806","article-title":"A framework for variation discovery and genotyping\nusing next-generation DNA sequencing data","volume":"43","author":"DePristo","year":"2011","journal-title":"Nat.\nGenet."},{"issue":"5","key":"2026091109082372000_cit32","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1093\/bioinformatics\/btx699","article-title":"Mosdepth: quick coverage calculation for genomes and\nexomes","volume":"34","author":"Pedersen","year":"2018","journal-title":"Bioinformatics"},{"key":"2026091109082372000_cit33","doi-asserted-by":"publisher","first-page":"D32","DOI":"10.1093\/nar\/gkj014","article-title":"ISfinder:\nthe reference centre for bacterial insertion sequences","volume":"34","author":"Siguier","year":"2006","journal-title":"Nucleic Acids Res."},{"issue":"2","key":"2026091109082372000_cit34","doi-asserted-by":"publisher","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program\nfor annotating and predicting the effects of single nucleotide polymorphisms,\nSnpEff: SNPs in the genome of Drosophila melanogaster strain w1118;\niso-2; iso-3","volume":"6","author":"Cingolani","year":"2012","journal-title":"Fly"},{"issue":"21","key":"2026091109082372000_cit35","doi-asserted-by":"publisher","first-page":"2987","DOI":"10.1093\/bioinformatics\/btr509","article-title":"A statistical\nframework for SNP calling, mutation discovery, association mapping\nand population genetical parameter estimation from sequencing data","volume":"27","author":"Li","year":"2011","journal-title":"Bioinformatics"},{"issue":"11","key":"2026091109082372000_cit36","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.1093\/bioinformatics\/btv070","article-title":"CNOGpro: detection\nand quantification\nof CNVs in prokaryotic whole-genome sequencing data","volume":"31","author":"Brynildsrud","year":"2015","journal-title":"Bioinformatics"},{"issue":"D1","key":"2026091109082372000_cit37","doi-asserted-by":"publisher","first-page":"D606","DOI":"10.1093\/nar\/gkz943","article-title":"The PATRIC Bioinformatics Resource Center: expanding\ndata and analysis capabilities","volume":"48","author":"Davis","year":"2019","journal-title":"Nucleic Acids\nRes."}],"container-title":["ACS Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsinfecdis.6c00339","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/12\/9\/3159\/67378667\/acsinfecdis.6c00339.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/12\/9\/3159\/67378667\/acsinfecdis.6c00339.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:27:25Z","timestamp":1789133245000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article\/12\/9\/3159\/5326865\/Fatty-Acid-Biosynthesis-Inhibitors-Fabimycin-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,24]]},"references-count":37,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,8,24]]},"published-print":{"date-parts":[[2026,9,11]]}},"URL":"https:\/\/doi.org\/10.1021\/acsinfecdis.6c00339","relation":{},"ISSN":["2373-8227"],"issn-type":[{"value":"2373-8227","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,24]]}}}