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SLS/WMS Micro Seminar: Disulfide bond formation underpins antimicrobial resistance in Enterobacteria, Dr Despoina Mavridou, Imperial College London
Abstract: Extracytoplasmic proteins assume their native structure with the help of chaperones and folding catalysts en route to their final location. Disulfide bond formation plays an integral part in this process, contributing to protein stability and function. Despite their simple chemistry, disulfide bonds are introduced into substrate proteins by dedicated folding pathways in most organisms. In the periplasm of Gram-negative bacteria this is performed by the DSB system, and more specifically by the oxidase DsbA. Although the function of the DSB proteins is well characterized and their role in bacterial pathogenesis has been discussed, their contribution to antimicrobial resistance (AMR) has never been explored. We have demonstrated that disulfide bond formation is necessary for the function of key antimicrobial resistance determinants in the cell envelope of Enterobacteria. More specifically, we have found that deletion of DsbA abrogates or severely affects the breakdown of β-lactam antibiotics by β-lactamases, resistance to polymyxins due to the activity of mobile colistin resistance (MCR) enzymes and intrinsic resistance to multiple antibiotics arising from the action of Resistance-Nodulation-Division (RND) efflux pumps. Such diverse resistance determinants are impaired because the absence of DsbA compromises stability and folding of β-lactamases and MCR enzymes, whilst also leading to altered periplasmic proteostasis indirectly impacting efflux pump function. Importantly, the DSB system is a tractable AMR target, as chemical inhibition of disulfide bond formation sensitizes multidrug-resistant clinical isolates to several classes of existing antibiotics. We are currently focused on the discovery of improved DsbA inhibitors since their generation could lead to the development of next-generation antibiotic adjuvants that would function as broad-acting resistance breakers.