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We previously developed small molecule inhibitors of DsbA from <jats:italic>Escherichia coli<\/jats:italic> K\u201012 (EcDsbA) and showed that they attenuate virulence of Gram\u2010negative pathogens by directly inhibiting multiple diverse DsbA homologues. Here we tested the evolutionary robustness of DsbA inhibitors as antivirulence antimicrobials against <jats:italic>Salmonella enterica<\/jats:italic> serovar Typhimurium under pathophysiological conditions in vitro. We show that phenylthiophene DsbA inhibitors slow <jats:italic>S<\/jats:italic>. Typhimurium growth in minimal media, phenocopying <jats:italic>S<\/jats:italic>. Typhimurium isogenic <jats:italic>dsbA<\/jats:italic> null mutants. Through passaging experiments, we found that DsbA inhibitor resistance was not induced under conditions that rapidly induced resistance to ciprofloxacin, an antibiotic commonly used to treat <jats:italic>Salmonella<\/jats:italic> infections. Furthermore, no mutations were identified in the <jats:italic>dsbA<\/jats:italic> gene of inhibitor\u2010treated <jats:italic>S<\/jats:italic>. Typhimurium, and <jats:italic>S<\/jats:italic>. Typhimurium virulence remained susceptible to DsbA inhibitors. Our work demonstrates that under in vitro pathophysiological conditions, DsbA inhibitors can have both antivirulence and antibiotic action. Importantly, our finding that DsbA inhibitors appear to be evolutionarily robust offers promise for their further development as next\u2010generation antimicrobials against Gram\u2010negative pathogens.<\/jats:p>","DOI":"10.1096\/fba.2020-00100","type":"journal-article","created":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T06:30:05Z","timestamp":1611037805000},"page":"231-242","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Antivirulence DsbA inhibitors attenuate <i>Salmonella enterica<\/i> serovar Typhimurium fitness without detectable resistance"],"prefix":"10.1096","volume":"3","author":[{"given":"Rabeb","family":"Dhouib","sequence":"first","affiliation":[{"name":"Institute of Health and Biomedical Innovation School of Biomedical Sciences Queensland University of Technology Herston QLD Australia"},{"name":"Centre for Immunology and Infection Control School of Biomedical Sciences Queensland University of 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