Mechanistic and structural insights into allosteric inhibitors of staphylococcal quorum sensing

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.