Design and Synthesis of Small-Molecule Inhibitors of Enteropathogenic Bacterial Virulence

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Abstract Enteric diarrheal disease continues to be a global health concern. Acute diarrhea is a leading cause of death in young children worldwide and is one of the most commonly reported illnesses in the United States. Enteric disease spreads quickly in areas lacking adequate sanitation and drinking water, as ingestion of the waterborne bacteria commonly results in vomiting and diarrhea, and subsequently, further contamination. The transcriptional cascade initiated by bacterial infection ultimately leads to the expression of virulence factors, including toxins, effector molecules, and colonization factors. It is by understanding the mechanism of bacterial virulence that we may understand the role of virulence factors in pathogenesis and identify effective therapeutics. Virulence-specific treatment methods would be especially significant given the rise in antimicrobial (drug) resistance. In particular, this study aims to exploit the fatty acid regulatory mechanism used by ToxT, a primary transcription factor involved in Vibrio cholerae virulence, to design a subset of compounds that may act as anti-virulence agents. The goals of the proposed research are to design and synthesize small-molecule inhibitors (Aim 1) and characterize their effects on the activity of ToxT (Aim 2) and other members of the AraC/XylS superfamily of proteins (Aim 3). Preliminary data supports our hypothesis that designing compounds that mimic the structure of the natural fatty acid ligand in ToxT in its protein-bound conformation will lead to potent ToxT inhibition. These studies will result in the synthesis and characterization of novel small molecules that specifically target V. cholerae virulence factors. Given the similarity of ToxT to virulence gene regulators in other bacteria, the proposed studies could also lead to effective drug candidates for numerous other enteric bacterial infections, including cholera, travelers' diarrhea, and dysentery.