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

Research output: Contribution to journalArticle

Authors

  • Jonathan A G Cox
  • Grace Mugumbate
  • Laura Vela-Glez Del Peral
  • Stefan Jackenkroll
  • Arancha Perez
  • Carlos Alemparte
  • Jorge Esquivias
  • Joël Lelièvre
  • Fernando Ramon
  • David Barros
  • Lluis Ballell

Colleges, School and Institutes

External organisations

  • Aston University
  • European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom, CB10 1SD.
  • Molecular Discovery Research, GlaxoSmithKline, Santiago Grisolia 4, 28760 Tres Cantos, Madrid, Spain.
  • Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain.
  • School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom.

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.

Details

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