Towards a pan‐group activator of the quorum sensing system in the common pathogen Staphylococcus epidermidis

Abstract

Quorum sensing (QS) is a chemical communication process that allows bacteria to regulate gene expression based on changes in population density and environmental cues, thereby enabling bacteria to coordinate their behaviors on a community‐wide scale. Among pathogens, QS is often found to play an important role in virulence. One such pathogen is the Gram‐positive bacteria Staphylococcus epidermidis. S. epidermidis is a leading cause of hospital‐acquired infections, and these infections are difficult to eradicate via traditional antibiotic therapy due to increasing antibiotic resistance and the formation of robust biofilms. The pathogenesis of S. epidermidis is mainly under the control of the accessory gene regulator (agr) QS system. agr activation is achieved by the binding of the cyclic peptide (an autoinducing peptide or AIP) signal to its cognate receptor AgrC. Synthetic compounds that target the agr system could represent valuable tools to elucidate the roles of QS and the agr system during S. epidermidis infections.S. epidermidis can be classified into three specificity groups (I, II, or III) based on the unique AIP sequence used by each group (AIP‐I, ‐II, or ‐III). A previous study characterizing the AIP‐I signal has yielded synthetic group‐specific and pan‐group inhibitors targeting the S. epidermidis agr system. The development of pan‐group activators of the agr system is of significant interest, however, as agr activation can reduce biofilm formation by S. epidermidis. To date, no such activators have been identified. The present study was directed toward the identification of synthetic pan‐group agr activators in S. epidermidis by studying and delineating the structure‐activity relationships (SARs) of AIPs‐I, ‐II, and ‐III. Our preliminary data show that the residues at the exocyclic tail region of AIP‐II and AIP‐III are important to maintain the efficacy and potency of the native AIPs, as well as the residues that are important for receptor activation, causing a switch in certain cases from activator to inhibitor. We have also identified endocyclic residues that are important to receptor binding and activation, as well as residues that are more tolerant to change. Utilizing the findings from these systematic SARs studies for all three native AIPs, we designed a small set of AIP analogs containing features hypothesized to be important for receptor activation in each agr group, and tested these AIP analogs in all three groups using reporter strains. From this focused set of AIP analogs, we discovered the first set of pan‐group activators of S. epidermidis agr system. Current efforts are directed toward improving the potency and the efficacy of these compounds, and their application to reduce biofilm accumulation of S. epidermidis on abiotic surfaces.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.