%0 Journal Article
%A Cox, Jonathan A. G.
%A Mugumbate, Grace
%A Vela González del Peral, Laura
%A Jankute, Monika
%A A. Abrahams, Katherine
%A Jervis, Peter
%A Jackenkroll, Stefan
%A Pérez, Arancha
%A Alemparte, Carlos
%A Esquivias, Jorge
%A Lelièvre, Joël
%A Ramón Olayo, Fernando Antonio
%A Barros, David
%A Ballell, Lluis
%A S. Besra, Gurdyal
%T Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen
%D 2016
%@ 2045-2322
%U https://hdl.handle.net/20.500.14352/23479
%X High-throughput phenotypic screens have re-emerged as screening tools in antibiotic discovery. The advent of such technologies has rapidly accelerated the identification of ‘hit’ compounds. A pre-requisite to medicinal chemistry optimisation programmes required to improve the drug-like properties of a ‘hit’ molecule is identification of its mode of action. Herein, we have combined phenotypic screening with a biased target-specific screen. The inosine monophosphate dehydrogenase (IMPDH) protein GuaB2 has been identified as a drugable target in Mycobacterium tuberculosis, however previously identified compounds lack the desired characteristics necessary for further development into lead-like molecules. This study has identified 7 new chemical series from a high-throughput resistance-based phenotypic screen using Mycobacterium bovis BCG over-expressing GuaB2. Hit compounds were identified in a single shot high-throughput screen, validated by dose response and subjected to further biochemical analysis. The compounds were also assessed using molecular docking experiments, providing a platform for their further optimisation using medicinal chemistry. This work demonstrates the versatility and potential of GuaB2 as an anti-tubercular drug target.
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