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

The expression of two major virulence factors of , cholera toxin (CT) and toxin co-regulated 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 (), TCP ( gene cluster), and other virulence genes. Unsaturated fatty acids (UFAs) and several small-molecule inhibitors of ToxT have been developed as antivirulence agents against . 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 strains containing various alleles. The fatty acids and virstatin had discrete effects depending on the ToxT allele (different by 2 amino acids), strain, and culture conditions, indicating that strains could overcome the effects of UFAs and small-molecule inhibitors by acquiring point mutations in . Our results suggest that small-molecule inhibitors should be examined thoroughly against various strains and alleles during development.