Targeting Bacterial Virulence Through Two-Component System Signaling (2021-04-23)

Abstract

Bacterial two-component systems (TCSs) are crucial for the translation ofcomplex molecular environments into microbial action. Prokaryotes have 20-120 distinct TCSs per organism and although ~50,000 TCS proteins have beenidentified from genomic sequences, most have not been characterized. Inparticular, much remains to be learned about the TCSs that controlpathogenesis and virulence in numerous organisms. This knowledge is criticalas the TCSs may serve as new antibacterial targets, which are desperatelyneeded. We have focused on P. aeruginosa infections, which have reached a"critical" threat status making novel therapeutic approaches required. We havedemonstrated the potential of TCS inhibition with benzothiazole-basedmolecules that perturb multiple virulence pathways in the burn wound P.aeruginosaisolate, PA14. Specifically, our compounds significantly reduce thelevel of toxic metabolites generated by this organism that are involved inquorum-sensing and redox-balancing mechanisms. They also decrease theability of this organism to swarm and attach to surfaces, likely by influencingtheir motility appendages. Transcript and proteomic analysis of inhibitor-treatedcultures showed substantial perturbations to multiple pathways includingexpression of response regulator GacA, a “super regulator” of virulence. Mostrecently, we have also demonstrated efficacy in Salmonella enterica serotypeTyphimurium, including resensitization to polymyxin antibiotics. Thesepromising results establish that blocking of bacterial signaling in Gram-negativebacteria has dramatic consequences on virulence behaviors and great potentialfor future therapeutic development.