Webminar: Fighting Antibiotic Resistance: How to Monitor Drug-Protein Interactions in the Bacterial Periplasm.

Abstract:

Rapid spread of antimicrobial resistance across bacterial pathogens poses a serious risk to the efficacy of available treatments. One of the promising strategies explored in the recent years concerns the use of b-lactam antibiotic together with b-lactamase inhibitor to re-sensitize antibiotic resistant, b-lactamase producers to available b-lactams. Understanding the action of these drug/inhibitor combinations is difficult due to presence of multiple competing interactions taking place in their site of action, that is periplasmic space delineated by the inner and outer membranes of Gram-negative bacteria.

In my talk, I will present our recent work describing an in-cell NMR-based research strategy to monitor the activity of the enzymes located in the periplasm. We demonstrate its unprecedented analytical power in monitoring in situ and in a real time (i) the hydrolysis of b-lactams by b-lactamases, (ii) the interaction of drugs belonging to the b-lactam family with their essential targets, and (iii) the binding of inhibitors to these enzymes. In-cell NMR that does not require purification and selective tagging of the studied enzymes, allows to evaluate the efficacy of new compounds, including drug/inhibitor combinations directly in their native environment. Therefore, this experimental strategy can be easily transferred to the investigation of new drugs or drug/inhibitor combinations targeting periplasmic proteins of antibiotic resistant pathogens.