News & Events
QseC inhibitors a novel strategy for development of anti-virulence microbial drugs
Speaker(s): Prof. Vanessa Sperandio, Departments of Microbiology and Biochemistry, University of Texas Southwestern Medical Center, USA.
When: 28 September 2016 (3:00 - 4:00pm)
Where: SBS Classroom 3 (Level 1)
Type: Seminars

Abstract

There is an imminent need for development of novel treatments for infectious diseases, given that one of the biggest challenges to medicine in the foreseeable future is the emergence of microbial antibiotic resistance. The rapid mutation rate of bacteria allows them to develop resistance to virtually all known antibiotics. This threat to humans and their food sources is immediate, global and potentially catastrophic.

Many bacterial pathogens exploit cell-to-cell signaling between the microbial flora and the host as a means to gage and recognize the host environment. This inter-kingdom signaling is predicated upon hormonal communication, and utilizes the host epinephrine and/or norepinephrine (NE) stress hormones and a bacterial aromatic hormone-like signal named autoinducer-3 (AI-3). This communication relies on a conserved membrane sensor, QseC, to sense and respond to these signals to initiate a complex signaling cascade to promote expression of virulence factors. We have also shown that inhibition of this signaling pathway by small molecules constitutes a novel and exciting approach to develop therapeutic strategies to hamper bacterial infections. LED209 (at a concentration of only 5pM) effectively blocks QseC recognition of epinephrine and norepinephrine, successfully blocks virulence gene expression and pathogenesis in EHEC, S. typhimurium and F. tularensis in vitro and in vivo (during animal infections), but do not interfere with pathogen growth, which leads to a milder evolutionary pressure towards development of drug resistance. This is a novel approach to antimicrobial drug development, QseC antagonists confuse or obfuscate signaling between bacteria and the host, and unlike antibiotics, do not kill or hinder bacterial growth. Hence, QseC antagonists should be viewed as blockers of pathogenicity (anti-virulence drugs) rather than as antimicrobials.