Project No. 2138

Primary Supervisor

Dr Christopher Mulligan – University of Kent

Co-Supervisor(s)

Prof Jonathan Essex – University of Southampton

Dr Mark Paget – University of Sussex

Summary

The alarming global progression of antimicrobial resistance threatens to propel humankind into a post-antibiotic era where illnesses and injuries that are currently trivial to treat become life-threatening conditions.

Even now, in the EU alone there are ~25,000 deaths per year directly associated with drug resistant bacteria. Unchecked, the global death toll could exceed 10 million deaths per year by 2050, even exceeding cancer-related deaths. Developing new antibiotics is essential, but this is slow and expensive, and the chances of bacteria developing resistance to these new drugs is high. An extremely promising, complementary approach to help combat resistance is to reduce resistance itself. By identifying pathways that, when disrupted, sensitise resistant bacteria to antibiotics, we could breathe new life into drugs rendered obsolete, and boost the potency of newly developed drugs.

The DedA family are integral membrane proteins that contribute to antibiotic resistance in clinically relevant pathogenic bacteria; including being essential for resistance to colistin, which is a drug of last resort used in the treatment of multidrug-resistant bacterial infections. Thus, DedA proteins present an attractive target in the pursuit of antibiotic potentiators. However, the DedA family is very mysterious; while hypothesised to be transport proteins, their structure, function, and physiological role are unknown.

In this project, we will use a multipronged approach to illuminate the physiological role of the DedA family. We will; assess the effects of gene knockout mutants in a variety of bacterial species using phenotype screening and proteomics; investigate DedA function using in vitro transport assays; determine DedA’s structural organisation using biochemical and biophysical approaches; and, use state-of-the-art computational approaches to investigate the antimicrobial mechanism of colistin, which will provide clues to DedA’s involvement in resistance. These findings will advance our understanding of this mysterious protein family, illuminate their role in antibiotic resistance, and develop the DedA family as targets for inhibition.