1. Academic Validation
  2. QseC inhibitors as an antivirulence approach for Gram-negative pathogens

QseC inhibitors as an antivirulence approach for Gram-negative pathogens

  • mBio. 2014 Nov 11;5(6):e02165. doi: 10.1128/mBio.02165-14.
Meredith M Curtis Regan Russell Cristiano G Moreira Adeniyi M Adebesin Changguang Wang 1 Noelle S Williams 1 Ron Taussig 2 Don Stewart 3 Philippe Zimmern 4 Biao Lu Ravi N Prasad Chen Zhu David A Rasko 5 Jason F Huntley 6 John R Falck Vanessa Sperandio 7
Affiliations

Affiliations

  • 1 Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.
  • 2 Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas, USA.
  • 3 Omm Scientific, Dallas, Texas, USA.
  • 4 Department of Urology, UT Southwestern Medical Center, Dallas, Texas, USA.
  • 5 Department of Microbiology and Immunology and the Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
  • 6 College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio, USA.
  • 7 vanessa.sperandio@utsouthwestern.edu.
Abstract

Invasive pathogens interface with the host and its resident microbiota through interkingdom signaling. The Bacterial receptor QseC, which is a membrane-bound histidine sensor kinase, responds to the host stress Hormones epinephrine and norepinephrine and the Bacterial signal AI-3, integrating interkingdom signaling at the biochemical level. Importantly, the QseC signaling cascade is exploited by many Bacterial pathogens to promote virulence. Here, we translated this basic science information into development of a potent small molecule inhibitor of QseC, LED209. Extensive structure activity relationship (SAR) studies revealed that LED209 is a potent prodrug that is highly selective for QseC. Its warhead allosterically modifies lysines in QseC, impairing its function and preventing the activation of the virulence program of several Gram-negative pathogens both in vitro and during murine Infection. LED209 does not interfere with pathogen growth, possibly leading to a milder evolutionary pressure toward drug resistance. LED209 has desirable pharmacokinetics and does not present toxicity in vitro and in rodents. This is a unique antivirulence approach, with a proven broad-spectrum activity against multiple Gram-negative pathogens that cause mammalian infections.

Importance: 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. Here, we devised a broad-spectrum antivirulence approach targeting a conserved histidine kinase, QseC, in several Gram-negative pathogens that promotes their virulence expression. The LED209 QseC inhibitor has a unique mode of action by acting as a prodrug scaffold to deliver a warhead that allosterically modifies QseC, impeding virulence in several Gram-negative pathogens.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-19748
    98.87%, 细菌QseC抑制剂