RT Journal Article
T1 Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen
A1 Cox, Jonathan A. G.
A1 Mugumbate, Grace
A1 Vela González del Peral, Laura
A1 Jankute, Monika
A1 Abrahams, Katherine A.
A1 Jervis, Peter
A1 Jackenkroll, Stefan
A1 Pérez, Arancha
A1 Alemparte, Carlos
A1 Esquivias, Jorge
A1 Lelièvre, Joël
A1 Ramón Olayo, Fernando Antonio
A1 Barros, David
A1 Ballell, Lluis
A1 Besra, Gurdyal S.
AB 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.
PB Springer Nature
SN 2045-2322
YR 2016
FD 2016
LK https://hdl.handle.net/20.500.14352/23479
UL https://hdl.handle.net/20.500.14352/23479
LA eng
NO Unión Europea. FP7
DS Docta Complutense
RD 4 abr 2025