Mechanistic and structural insights into allosteric inhibitors of staphylococcal quorum sensing

Lead Research Organisation: University of Nottingham
Department Name: Sch of Pharmacy

Abstract

One of the major global challenges in modern medicine is the unprecedented rate of increase in antimicrobial resistance (AMR) in bacteria to most if not all known classes of antibiotics. Conventional antibiotics that exert either bacteriostatic or bactericidal effects imposing immerse selective pressure on the bacteria, hence the development of AMR is inevitable. Thus, alternative therapeutic approaches are required. In this context, anti-virulent agents that act by 'disarming' the bacteria, thus impose no apparent selective pressure, is a promising novel approach.

We have recently discovered a chemical agent that displayed potent negative allosteric modulation of staphylococcal quorum sensing. This mechanism of action is unique and not previously observed. Moreover, the chemical agent showed significant negative impact on another strand of the staphylococcal quorum sensing system. A detailed structural insight into the binding sites will be obtained by using modern molecular biology techniques, e.g. site-specific mutagenesis of the target proteins followed by ligand binding assays. These results will inform on the design of new chemical analogues, which will be constructed by total chemical synthesis and evaluated for their inhibitory activity.

Publications

10 25 50

Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M008770/1 01/10/2015 30/09/2023
1803747 Studentship BB/M008770/1 01/10/2016 23/12/2020 James Reekes
 
Description Have synthesised analogues of our lead natural product as part of a structure activity relationship study for the development of novel anti-virulence compounds for the treatment of MRSA infection.
Exploitation Route Develop further inhibitors of MRSA virulence
Sectors Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology