Biophysical Society Thematic Meeting | Stockholm 2022

Physical and Quantitative Approaches to Overcome Antibiotic Resistance

Monday Speaker Abstracts

THE TWO-FACED JANUS OF MULTIDRUG EFFLUX SUBSTRATES AND INHIBITORS Helen I Zgurskaya 1 ; 1 University of Oklahoma, Chemistry and Biochemistry, Norman, OK, USA Antibiotics are miracle drugs that can cure infectious bacterial diseases. However, their utility is challenged by antibiotic resistant bacteria emerging in clinics. Such bacteria as Gram-negative and Mycobacteriales species are intrinsically resistant to most clinical antibiotics and can further gain multidrug resistance through mutations and plasmid acquisition. These species stand out by the presence of additional external outer membranes (OM). Although formidable, the OM is a passive permeability barrier that can reduce penetration of antibiotics but cannot affect intracellular steady-state concentrations of drugs. The two-membrane envelopes are further reinforced by active efflux transporters that expel antibiotics from cells against their concentration gradients. Active efflux of drugs is the major mechanism of antibiotic resistance in bacterial pathogens that act synergistically with the low permeability barrier of the OM. In this presentation, we summarize the progress in understanding the mechanism of efflux pumps from Resistance-Nodulation-Division (RND) superfamily and their kinetic advantages from synergistic relationships with passive permeation barriers. The ability to transfer various substrates across the OM at the expense of the proton-motive force acting on the inner membrane and engagement of accessory proteins for their functions are the major mechanistic advantages of these pumps. Both the RND transporters and their accessory proteins are targeted in the discovery of efflux pump inhibitors that in combinations with antibiotics potentiate antibacterial activities. We discuss intriguing relationships between substrates and inhibitors of efflux pumps, as both types of ligands face similar barriers and binding sites in the transporters and accessory proteins and both types of activities are often present in the same chemical scaffold. Recent mechanistic insights, both empirical and computational, led to identification of features that distinguish efflux pump inhibitors from the substrates. These findings suggest the path for optimization of efflux inhibitory activities in antibiotics and other chemically diverse compounds.

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