Synthetic Peptides Capable of Potent Multigroup Quorum Sensing Activation and Inhibition in Both Cultures and Biofilm Communities.

The pathogen uses a chemical signaling process, i.e., quorum sensing (QS), to form robust biofilms and cause human infection. Many questions remain about QS in , as it uses this intercellular communication pathway to both negatively and positively regulate virulence traits. Herein, we report synthetic multigroup agonists and antagonists of the accessory gene regulator () QS system capable of potent superactivation and complete inhibition, respectively. These macrocyclic peptides maintain full efficacy across the three major specificity groups, and their activity can be "mode-switched" from agonist to antagonist via subtle residue-specific structural changes. We describe the design and synthesis of these non-native peptides and demonstrate that they can appreciably decrease biofilm formation on abiotic surfaces, underscoring the potential for agonism as a route to block virulence. Additionally, we show that both the agonists and antagonists are active in , another common pathogen with a related system, yet only as antagonists. This result not only revealed one of the most potent inhibitors known in but also highlighted differences in the mechanisms of agonism and antagonism between these related bacteria. Finally, our investigations reveal unexpected inhibitory behavior for certain agonists at sub-activating concentrations, an observation that can be leveraged for the design of future probes with enhanced potencies. Together, these peptides provide a powerful tool set to interrogate the role of QS in infections and in pathogenicity in general.