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



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Cox, Jonathan A. G. and Mugumbate, Grace and Vela González del Peral, Laura and Jankute, Monika and A. Abrahams, Katherine and Jervis, Peter and Jackenkroll, Stefan and Pérez, Arancha and Alemparte, Carlos and Esquivias, Jorge and Lelièvre, Joël and Ramón Olayo, Fernando Antonio and Barros, David and Ballell, Lluis and S. Besra, Gurdyal (2016) Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen. Scientific Reports, 6 (38986). ISSN 2045-2322

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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.

Item Type:Article
Uncontrolled Keywords:Mycobacterium tuberculosis GuaB2; phenotypic screen
Subjects:Medical sciences > Biology
Medical sciences > Biology > Molecular biology
Medical sciences > Biology > Microbiology
ID Code:46387
Deposited On:08 Feb 2018 17:14
Last Modified:09 Feb 2018 09:47

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