Using chemical modification of a novel antimicrobial drug scaffold to reduce efflux from multridrug resistant Gram-negative ESKAPE pathogens

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Multidrug resistant pathogens have emerged as a major concern for public health and there are particular concerns about the emergence of a number of Gram-negative pathogens, for which there are dwindling treatment options and few compounds are in development stage. These pathogens are characterised by the ability to rapidly develop and/or acquire resistance mechanisms in response to exposure to different antimicrobial agents. A key part of the armoury of these pathogens are a series of efflux pumps, which effectively exclude or reduce the intracellular concentration of a large number of antibiotics, making the pathogens significantly more resistant. These efflux pumps are the topic of considerable interest, both from the perspective of basic understanding of efflux pump function, but also as targets for novel adjunct therapies. The proposed project will use a novel series of antimicrobial drugs to identify groups that inhibit removal from the cell, looking to link structure-function of the compounds with efflux.An ongoing collaboration between Kings College London and Public Health England has identified a new class of compounds with activity against key Gram-negative pathogens, including Klebsiella pneumoniae, Acinetobacter bauamnnii and Pseudomonas aeruginosa. As part of the development of the chemical series, the project team have identified that certain compounds are subject to efflux from the cell, this being inhibitable by known efflux pump inhibitors. Some members of the chemical series appear not to be subject to efflux, suggesting that the specific modifications on these drugs has altered their ability to be substrates for the respective efflux pumps. The student will explore the phenomenon, aiming to link structure-activity relationships in the chemical series with efflux by specific pumps.