Optimization of a novel series of pyranopyridine RND efflux pump inhibitors

The rise of multidrug resistant (MDR) Gram-negative pathogens complicates our ability to treat bacterial infections with antibiotics. MDR efflux pumps play a major role in the acquisition and expression of the MDR phenotype. The major MDR efflux pumps in Gram-negative pathogens are the resistance-nodulation-division (RND) superfamily pumps. Efflux pump inhibitors (EPIs) that target RND superfamily pumps could play an important role in the clinic as an adjunctive therapy to increase antibiotic efficacy, decrease resistance, and attenuate virulence in Gram-negative pathogens. Here, we review recent advances in the discovery and structurally enabled optimization of a novel series of RND-targeting pyranopyridine EPIs currently in the early stages of lead optimization.