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

Jonathan A G Cox, Grace Mugumbate, Laura Vela-Glez Del Peral, Monika Jankute, Katherine A Abrahams, Peter Jervis, Stefan Jackenkroll, Arancha Perez, Carlos Alemparte, Jorge Esquivias, Joël Lelièvre, Fernando Ramon, David Barros, Lluis Ballell, Gurdyal S Besra

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)
128 Downloads (Pure)

Abstract

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.

Original languageEnglish
Article number38986
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 16 Dec 2016

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