New boronate drugs and evolving NDM-mediated beta-lactam resistance
Olga Lomovskaya, Ruslan Tsivkovski, Maxim Totrov, Dana C. Dressel, Mariana Castanheira, Michael Dudley
Abstract
Taniborbactam and xeruborbactam are dual serine-/metallo-beta-lactamase inhibitors (BLIs) based on a cyclic boronic acid pharmacophore that undergo clinical development. Recent report demonstrated that New Delhi metallo-beta-lactamase (NDM)-9 (differs from NDM-1 by a single amino acid substitution, E152K, evolved to overcome Zn (II) deprivation) is resistant to inhibition by taniborbactam constituting pre-existing taniborbactam resistance mechanism. Using microbiological and biochemical experiments, we show that xeruborbactam is capable of inhibiting NDM-9 and propose the structural basis for differences between two BLIs.
Topics & Concepts
PharmacophoreBeta-lactamSerineBETA (programming language)ChemistryStereochemistryBoronic acidBiochemistryBiologyCombinatorial chemistryAntibioticsEnzymeComputer scienceProgramming languageAntibiotic Resistance in BacteriaTuberculosis Research and EpidemiologyOral and gingival health research