An ambitious long-term programme of multidisciplinary research with two closely linked objectives is proposed to support antimicrobial drug development. Firstly, to advance understanding, at the molecular level, of fundamental and important aspects of the biology of Gram-negative bacteria using the important pathogen model Pseudomonas aeruginosa. Secondly, and most important, to exploit our discoveries and develop ligands and inhibitors (hit and lead compounds) with the potential to underpin the discovery of improved therapies for Gram-negative infections. The research covers five distinct areas, or work packages. (WPI) The experimental validation and therefore identification of novel targets by gene knockout in P. aeruginosa. (WPII) Cloning, characterisation, biochemical and structural biology, of the novel targets. (WPIII) A directed, search for ligands/inhibitors, exploiting data from WPI and WPII, for these validated antimicrobial drug targets by virtual screening (VS) and assessment of druggabilty, high-throughput screening (HTS) of a carefully prioritised subset of targets. (WPIV) The characterisation of the interactions formed between the drug target and the ligand/inhibitor by biochemical and crystallographic study, computational modelling and then design and modelling to enhance binding properties. (WPV) The initial biological testing for efficacy against Gram-negative bacteria.
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