Dhouib, Rabeb, Vagenas, Dimitrios, Hong, Yaoqin, Verderosa, Anthony D., Martin, Jennifer L., Heras, Begoña, and Totsika, Makrina (2021) Antivirulence DsbA inhibitors attenuate Salmonella enterica serovar Typhimurium fitness without detectable resistance. FASEB BioAdvances, 3 (4). pp. 231-242.

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Abstract

Inhibition of the DiSulfide Bond (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.

Item ID:	83811
Item Type:	Article (Research - C1)
ISSN:	2573-9832
Keywords:	antimicrobial resistance, disulfide bond, enzyme inhibitors, experimental evolution, infection
Copyright Information:	© 2021 The Authors. FASEB BioAdvances published by the Federation of American Societies for Experimental Biology This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Funders:	National Health and Medical Research Council (NHMRC)
Projects and Grants:	NHMRC APP1144046, NHMRC APP1099151
Date Deposited:	16 Oct 2024 06:01
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