English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Open

Presents the pdf analysis as premium feature

PDF Analysis

Insights

Presents the summarisation as premium feature

Summarisation

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the zaia usage as premium feature

ZAIA

Zendy Tools

Zendy Plus

Presents the access of premium content as premium feature

Premium Content

Inhibition of the  D i S ulfide  B ond (DSB) oxidative protein folding machinery, a major facilitator of virulence in Gram‐negative bacteria, represents a promising antivirulence strategy. We previously developed small molecule inhibitors of DsbA from  Escherichia coli  K‐12 (EcDsbA) and showed that they attenuate virulence of Gram‐negative pathogens by directly inhibiting multiple diverse DsbA homologues. Here we tested the evolutionary robustness of DsbA inhibitors as antivirulence antimicrobials against  Salmonella enterica  serovar Typhimurium under pathophysiological conditions in vitro. We show that phenylthiophene DsbA inhibitors slow  S . Typhimurium growth in minimal media, phenocopying  S . Typhimurium isogenic  dsbA  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  Salmonella  infections. Furthermore, no mutations were identified in the  dsbA  gene of inhibitor‐treated  S . Typhimurium, and  S . 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‐generation antimicrobials against Gram‐negative pathogens.

Antivirulence DsbA inhibitors attenuate Salmonella enterica serovar Typhimurium fitness without detectable resistance