Synthesis and Lead Optimization of a Novel Inhibitor to Quorum Sensing Regulated Virulence in Vibrio cholerae

Abstract

Vibrio cholerae is the causal agent of the disease, cholera, which is responsible for 3-5 million infections and 100,000-120,000 deaths annually. Current treatments of cholera rely on the heavy use of antibiotics, but the status quo is not sustainable with the accelerating emergence of widespread antibiotic resistance in bacteria. Thus, an alternative strategy involving interference with V. cholerae’s quorum sensing system, a mechanism that regulates collective gene expression of biofilm formation and virulence factor production, is investigated. The goal is to attenuate virulence rather than kill the bacteria, thereby reducing the selective pressures that breed antibiotic resistance. Recently, a set of small molecule inhibitors to LuxO, a protein within V. cholerae’s quorum sensing circuit, was identified through a high-throughput screen. This work makes progress on the synthesis and lead optimization of one of these inhibitors. An efficient three-step synthetic scheme is proposed, and a small collection of analogs is designed using Structure-Activity Relationship (SAR) analysis and considerations from a medicinal chemistry perspective. Unfortunately, biological testing of the analogs seems to suggest that the binding pocket on LuxO does not tolerate even small modifications to the structure of Hit #26. On the other hand, the mechanism of action of Hit #26 is highly interesting, as it was found to be uncompetitive. Hit #26 is the first confirmed lead hit from the high-throughput screen that does not inhibit competitively, making it a unique potential drug candidate as well a useful tool for investigating LuxO.