Development of Chemical Tools to Study Quorum Sensing in Streptococcus mutans

Abstract

Streptococcus mutans, a Gram-positive major dental caries pathogen, uses a quorum sensing (QS) system called the competence regulon to colonize the oral cavity and compete with other oral commensal bacteria. QS is a cell-density based communication method bacteria use to regulate gene expression in relation to their population density. S. mutans uses two peptide pheromones, competence stimulating peptide (CSP) and comX-inducing peptide (XIP) as QS regulators. After secretion, CSP is processed by a membrane-localized protease, SepM and then interacts with the cognate transmembrane receptor ComD. XIP is active in chemically defined media (CDM) and after uptake by oligopeptide permease, XIP interacts with a cytosolic receptor ComR. The aim of this study was to develop CSP-based and XIP-based QS modulators that can either activate or inhibit S. mutans QS. To this end, I have performed a systematic structure-activity relationship (SAR) analysis of both CSP and XIP and identified several key structural features that are important for CSP:SepM, CSP:ComD and XIP:ComR interactions. Based on these SAR studies, I established the minimal structural requirements for CSP and XIP activity and rationally designed CSP-based QS activators with activities at the picomolar range and XIP-based QS inhibitors. My studies will help to understand S. mutans QS and lay the foundation to design QS-based therapeutics against S. mutans infections.