4 Year MRC PhD Programme: Bacterial efflux pumps and their potential as new targets for antimicrobials

The World Health Organisation has highlighted a priority list of drug resistant bacteria, the vast majority of which are Gram-negative. In clinical environments, multi-drug resistant Gram-negative bacterial infections presently account for 80% of all severe bacterial infections. New antibacterials are urgently needed, but out of all new antibiotic compounds in the pipeline nearly none display any activity against Gram-negative pathogens. The multi-layered cell envelope of Gram-negative organisms represents a formidable barrier for the uptake of antibiotics. Following permeation through porin channels, the vast majority of drugs are collected directly from the periplasm or the cytoplasm by multi-drug efflux pumps. The overexpression of active efflux pumps, sometimes acting in concert with mutations in the porin channels, prevents drugs from accumulating in the cells. In many cases, active drug efflux is the major factor driving antimicrobial resistance in Gram-negative bacteria.

This project will investigate the mechanistic determinants of efflux pump and porin function by a combination of molecular dynamics simulations, cryo-EM structure analysis and electrophysiology measurements. In addition, machine-learning approaches will be employed to determine the probability of an antibiotic compound to accumulate in the bacterial cell and thereby reach its drug target. We also aim to elucidate the chemical features that enhance uptake and avoid efflux pumps, informing future development of new antibiotics.