Variations in the Antivirulence Effects of Fatty Acids and Virstatin against Vibrio cholerae Strains.

Abstract

The expression of two major virulence factors of Vibrio cholerae, cholera toxin (CT) and toxin coregulated pilus (TCP), is induced by environmental stimuli through a cascade of interactions among regulatory proteins known as the ToxR regulon when the bacteria reach the human small intestine. ToxT is produced via the ToxR regulon and acts as the direct transcriptional activator of CT (ctxAB), TCP (tcp gene cluster), and other virulence genes. Unsaturated fatty acids (UFAs) and several smallmolecule inhibitors of ToxT have been developed as antivirulence agents against V. cholerae. This study reports the inhibitory effects of fatty acids and virstatin (a small-molecule inhibitor of ToxT) on the transcriptional activation functions of ToxT in isogenic derivatives of V. cholerae strains containing various toxT alleles. The fatty acids and virstatin had discrete effects depending on the ToxT allele (different by 2 amino acids), V. cholerae strain, and culture conditions, indicating that V. cholerae strains could overcome the effects of UFAs and small-molecule inhibitors by acquiring point mutations in toxT. Our results suggest that small-molecule inhibitors should be examined thoroughly against various V. cholerae strains and toxT alleles during development.