Antibacterial Drug Discovery (ADD) at Leeds

Novel strategies and methodology for antibacterial discovery It’s this problem that drives the research activities in my lab. When we’re not out basking in the near-tropical yorkshire sunshine, we are working to both understand and to address the problems of antibiotic resistance. Novel strategies and methodology for antibacterial discovery Microbiological evaluation (e.g. potency, selectivity, cidality, spectrum, antibiofilm activity, resistance potential) Elucidation/ confirmation of mode of action (microbiological, biochemical, structural; ruling out off-target effects)

A diversified approach to ADD Rational and computer-aided design of enzyme inhibitors directed at both established and new bacterial targets (e.g. PMIDs: 25137573, 27499424, 25619596, 29271657, 29456792) [Professor Colin Fishwick (CF) and Dr Alex O’Neill (AO)] Rational chemical modification of existing clinically-deployed antibiotics to expand their spectrum of activity to encompass Gram-negative pathogens (unpublished) [CF and AO] Repurposing compounds for the treatment of bacterial infection that have an established history of safe human use outside antibacterial chemotherapy (e.g. 30590494, 25368206, 27121399) [AO] Natural product discovery, including revisiting unexploited antibiotics in search of antibacterial drug candidates (e.g. 29234001, 27899790) [AO and Professor Chris Rayner], and discovery of new natural antibiotics from non-canonical sources (unpublished) [AO] Use of Leeds-developed Affimer (artificial binding protein) technology (28654419) to generate antibacterial inhibitors or agents that restore antibiotic sensitivity in multidrug-resistant bacteria (unpublished) [Dr Darren Tomlinson and AO]

Addressing bottlenecks in ADD How to deliver inhibitors into bacteria? Research projects sponsored by MRC/ BBSRC totaling £2M working to understand; how existing antibiotics get into bacteria [Dr Alex O’Neill (AO)] how the outer membrane of Gram-VE bacteria is assembled [Professor Neil Ranson and Prof Sheena Radford] How to discover new natural product antibiotics? development of platform technologies for switching on cryptic secondary metabolism in streptomycetes [Dr Ryan Seipke and AO] validating novel, non-canonical sources of natural product antibiotics [AO] Generating new tools and knowledge to streamline the discovery process assays to aid rapid removal of nuisance compounds from screening campaigns (15531595) generation and use of whole-cell biosensors for rapid determination of mode of action (21282422, 19298367)

Expertise and facilities to underpin ADD Medicinal chemistry, including experience with natural products structure-based drug design and synthesis in silico screening chemical optimization of scaffolds natural product purification and chemical characterization Structural biology world-leading expertise and capabilities in cryo-EM, X-ray crystallography and NMR bolstered by £17M investment in 2016 to include 2 X 300 Kv Titan Krios and 950 MHz NMR In vivo testing of ADCs (via existing collaborators)