Mechanism and structure of the PACE family of transport proteins

Co-supervisor Dr David Kelly, University of Sheffield

Resistance of bacterial pathogens to drugs is a worldwide challenge to human health. Drug efflux mediated by membrane transport proteins is a significant mechanism of resistance. Recently Peter Henderson, with Ian Paulsen and Karl Hassan in Australia, characterised a novel family of drug efflux pumps, called the Proteobacterial Antimicrobial Compound Efflux (PACE) family. At least two of
these conferred resistance to the antiseptic chlorhexidine, widely used in hospitals and proprietary medicines. In Leeds Peter and Adrian Goldman expressed 17 homologues from various bacteria, including serious pathogens like Acinetobacter, Klebsiella, Pseudomonas, Salmonella and Burkholderia in E. coli. Seven PACE efflux proteins were subsequently purified in sufficient quantities for mechanistic and structural analyses, and more will be isolated and characterised. The project brings together expertises in structural biology (Adrian
Goldman), bacterial resistance to antibiotics (David Kelly), and membrane transport (Peter Henderson) to illuminate the mechanistic biology of a previously unknown family of multidrug resistance proteins. The student will have access to
world leading facilities in the Astbury Centre for Structural Molecular Biology at Leeds and in the Department of Molecular Biology and Biotechnology in Sheffield. Candidates should have a good degree in Molecular Biology, Microbiology, Biochemistry or Chemistry.