Optimizing Agonists of Vibrio cholerae Quorum Sensing: Implications for Disease Treatment

Abstract

Vibrio cholerae, the etiological agent of the disease cholera, utilizes a bacterial communication system called quorum sensing (QS) to coordinate biofilm formation and virulence factor production. QS depends on small molecules called autoinducers that bind to protein receptors and elicit population wide responses through the collective activation or repression of specific genes. The native autoinducer of V. cholerae, CAI-1, binds to the histidine kinase receptor CqsS. Since binding of CAI-1 to CqsS results in inhibition of virulence factor production and reduced pathogenicity, we sought to create an optimally potent agonist of the CqsS receptor to develop as a quorum sensing therapeutic. We pursued two different approaches to achieve this goal. For the first project, we combined functional groups previously shown to increase agonist activity on CqsS into one molecule. For the second project, we conducted a High Throughput Screening (HTS) of potential CqsS agonists to identify active molecules. We then created a small focused library to examine which features of these molecules were important for agonist activity. Through the first project, we were able to identify the most potent CqsS agonist to date. We proceeded to an animal study of the effect of a structurally similar molecule on cholera disease. Findings were inconclusive, likely because the molecule was unable to reach the site of infection. For the second project, we have identified key structures that are important to the activity of the molecule and suggest a second library of analogues. As QS offers an alternative to antibiotic therapy of cholera, we sought to understand the use of antibiotics for cholera and the current spectrum of antibiotic resistance through a separate project in Bangladesh. This study revealed that antibiotics are important for treating cholera in a resource-poor setting and that the spectrum of antibiotics to which V. cholerae is resistant is increasing. Therefore there is a pressing need to develop alternative therapies, such as QS manipulation, to combat endemic antibiotic resistant cholera.