Probing the physiological role and mechanism of DedA proteins, an integral membrane protein family critical to viability and antimicrobial resistance

Antimicrobial resistance is a major global health concern. The DedA family are integral membrane proteins involved in resistance to several antimicrobials in clinically relevant pathogens, including Pseudomonas aeruginosa and Klebsiella pneumoniae. A DedA protein in K. pneumoniae was recently shown to be essential for resistance to colistin, a drug of last resort used in the treatment of multidrug-resistant bacterial infections. In addition, there is emerging evidence that DedA proteins are essential for bacterial viability. Therefore, inhibiting the function of DedA proteins could sensitise bacteria to currently available antibiotics and may also provide the basis for new antibiotic development. However, the development of DedA inhibitors is beleaguered by our lack of understanding of DedA structure and mechanism or even a clear idea of their role in AMR and bacterial physiology. The goal of this multidisciplinary and collaborative project is to investigate the physiological role of DedA proteins using an array of microbiological approaches, and use protein biochemistry and biophysical methods to probe the structure and functional activity of DedA proteins in vitro.