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

• Published in: Scientific reports Vol. 6; no. 1; p. 38986
• Main Authors: Cox, Jonathan A G, Mugumbate, Grace, Del Peral, Laura Vela-Glez, 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: Journal Article
• Language: English
• Published: England Nature Publishing Group 16.12.2016
• Subjects: Antitubercular Agents - pharmacology; Bacillus Calmette-Guerin vaccine; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; BCG; Biochemical analysis; Drug Evaluation, Preclinical; Enzyme Inhibitors - pharmacology; IMP Dehydrogenase - antagonists & inhibitors; IMP Dehydrogenase - genetics; IMP Dehydrogenase - metabolism; Inosine monophosphate; Mycobacterium bovis - enzymology; Mycobacterium bovis - genetics; Mycobacterium tuberculosis - enzymology; Mycobacterium tuberculosis - genetics; Pharmaceutical sciences; Tuberculosis
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep38986

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.