Multidrug resistant (MDR) infections are a global healthcare crisis. In Staphylococcus aureus and several other clinical pathogens, resistance has emerged to all classes of antimicrobial agents, including antibiotics and hospital-grade antiseptics. Extrusion of antimicrobial compounds by bacterial multidrug efflux pumps is a of the major causes of failure of drug-based treatments as bacteria can evade the effects of multiple structurally different compounds simultaneously. However, very little is currently known about the function and substrate range of these efflux pumps. This project will examine different multidrug efflux pumps to uncover the structural basis of substrate specificity and transport. It will examine the impact of bacterial membrane modifications on bacterial multidrug efflux pump function, and how peptide- and/or polymer-based antimicrobials inhibit multidrug efflux pumps and disrupt membrane integrity. Other avenues of investigation include characterising the effect of lipid modifications in antimicrobial resistance, and computational drug design of lead new candidates for antimicrobial design. This project requires good collaboration skills, a broad understanding of biochemistry, and microbiology, and a willingness to learn skills in computational chemistry. It uses a range of computational techniques, primarily multiscale molecular dynamics simulations, supported by experimental collaborations.

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