Extending the Potency and Lifespan of Antibiotics: Inhibitors of Gram-Negative Bacterial Efflux Pumps

The Global Antibiotic Research & Development Partnership (GARDP) accelerates the development and access of treatments for drug-resistant infections. Together with public, private, and non-profit partners, GARDP works in partnership to develop new antibiotics and expand access to them. Through our Discovery & Exploratory Research (DER) programme, GARDP focuses on the search for novel molecules and new bacterial targets against WHO-critical Gram-negative bacterial pathogens. This work contributes to the global antibiotic R&D pipeline, aiming to create a steady stream of promising new candidate drugs. One research area of the DER programme focuses on the discovery of potentiating compounds that can restore the activity of clinical antibiotics lost to resistance, such as efflux inhibitors.

Many antibiotics are substrates of bacterial efflux pumps, and modifications to the structure or overexpression of efflux pumps are an important resistance mechanism used by many multidrug-resistant bacteria. Therefore, chemical inhibition of bacterial efflux to revitalize existing antibiotics is considered a promising approach for antimicrobial chemotherapy. We recently provided an overview of clinically relevant multidrug resistance efflux pumps in Gram-negative bacteria and further described over 50 efflux inhibitors that target such systems. Following our medicinal chemistry and microbiology review, we selected promising efflux inhibitors for benchmarking, using a K. pneumoniae ∆ramR mutant with decreased susceptibility to antibiotics effluxed by the AcrAB-TolC system. The results will determine if these compounds are viable starting points for hit-to-lead projects focused on efflux inhibition in Gram-negative bacteria.