Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen

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 pro...

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Main Authors: Cox, Jonathan A G, Mugumbate, Grace, Peral, Laura Vela-Glez Del, Jankute, Monika, Abrahams, Katherine A, Jervis, Peter, Jackenkroll, Stefan, Perez, Arancha, Alemparte, Carlos, Esquivias, Jorge, Lelièvre, Joël, Ramon, Fernando, Barros, David, Ballell, Lluis, Besra, Gurdyal S
Format: Article
Language:English
Published: Nature Research 2022
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Online Access:https://www.nature.com/articles/srep38986
http://hdl.handle.net/11408/4905
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Summary: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.