Eszter Lodinsky
AcrAB-TolC is a member of the Resistance-Nodulation-cell Division superfamily of efflux pumps that is notorious for their wide substrate specificity and role in multidrug resistance. The complex harnesses the energy of a proton motive force in order to carry out its function. I aim to elucidate this complex pathway and gain deeper insight into how protonation in the core of the inner membrane leads to the conformational changes required for drug efflux in the periplasmic space. Using a combination of a biochemical and structural approaches, I will look at the phenotypic effects of different mutations and evaluate the underlying structural changes.
Daitian Xu
My project aim is to develop structure-based inhibitors of bacterial efflux pumps to restore antibiotic efficacy against multi-drug resistant Gram-negative bacteria, particularly Escherichia coli and Klebsiella pneumoniae. Efflux pumps like AcrAB-TolC contribute to antibiotic resistance by actively expelling drugs from bacterial cells. Using single-particle cryo-EM and biochemical assays, I investigate the structural mechanisms of inhibitor-resistant AcrB variants and design optimized pyridylpiperazine-based inhibitors (PyrPips) with enhanced affinity and specificity. By overcoming efflux pump-mediated resistance, this project provides a promising strategy to extend the clinical lifespan of existing antibiotics and combat the growing global threat of antimicrobial resistance.