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 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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Divisions: College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences > Cell & Tissue Biomedical Research
Additional Information: © The Author(s) 2016. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit Funding: Personal Research Chair from Mr. James Bardrick, a Royal Society Wolfson Research Merit Award; MRC (MR/K012118/1); FP7-2007–2013 (ORCHID no. 261378); BBSRC for an Industrial CASE Studentship in collaboration with the Institute of Microbiology and Infection, University of Birmingham and Diseases of the Developing World, GSK, Tres Cantos, Madrid; and EMBL and Marie Curie Actions.
Publication ISSN: 2045-2322
Last Modified: 03 Jun 2024 07:24
Date Deposited: 17 Jan 2017 15:30
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2016-12-16
Accepted Date: 2016-11-16
Submitted Date: 2016-07-06
Authors: Cox, Jonathan A.G. (ORCID Profile 0000-0001-5208-4056)
Mugumbate, Grace
Vela-Glez del Peral, Laura
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.



Version: Published Version

License: Creative Commons Attribution

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