Publication of the week: Professor Paul Finn

N. Velikova, S. Fulle, A.S. Manso, M. Mechkarska, Paul Finn, J.M. Conlon, M.R. Oggion, J.M. Wells & A. Marina, “Putative histidine kinase inhibitors with antibacterial effect against multi-drug resistant clinical isolates identified by in vitro and in silico screens”, Scientific Reports 2016, 6:26085. doi:10.1038/srep26085.

New antibiotics are urgently needed to address the growing problem of bacterial resistance to current drugs. This topic is of great public concern and barely a week passes without news of a new problematic pathogen or a speech from a senior politician or medical expert warning of the potential to return to a pre-antibiotic era.

This study reports work on a bacterial signalling pathway, called two-component systems (TCS). These are widely used by bacteria to regulate gene expression in response to various environmental stimuli and physiological stress and have been previously proposed as promising antibacterial targets. TCS consist of a sensor histidine kinase (HK) and an effector response regulator. The article describes the identification of putative HK inhibitors following two independent experimental approaches: in vitro fragment-based screen via differential scanning fluorimetry and in silico structure-based screening, each followed up by the exploration of analogue compounds as identified by ligand-based similarity searches.

Nine of the tested compounds showed antibacterial effect against multi-drug resistant clinical isolates of bacterial pathogens. Overall, putative HK autophosphorylation inhibitors were found that together provide a promising starting point for further optimization towards novel antibacterial drugs.

Read the full article on the Nature website or download the PDF (2MB).

Professor Paul Finn is Professorial Research Fellow in the Clore Laboratory and Department of Applied Computing. He is also CEO of InhibOx, a spin-out company from the Chemistry Department of the University of Oxford focused on computer-aided drug design, and runs a drug design consultancy Affinity Drug Design.