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oai:docta.ucm.es:20.500.14352/234792024-06-27T16:15:39Zcom_20.500.14352_14col_20.500.14352_15

Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen Cox, Jonathan A. G. Mugumbate, Grace Vela González del Peral, Laura Jankute, Monika Abrahams, Katherine A. Jervis, Peter Jackenkroll, Stefan Pérez, Arancha Alemparte, Carlos Esquivias, Jorge Lelièvre, Joël Ramón Olayo, Fernando Antonio Barros, David Ballell, Lluis Besra, Gurdyal S. 579.873.21 579.8 Mycobacterium tuberculosis GuaB2 phenotypic screen Biología Biología molecular (Biología) Microbiología (Biología) 24 Ciencias de la Vida 2415 Biología Molecular 2414 Microbiología 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. Unión Europea. FP7 Sección Deptal. de Bioquímica y Biología Molecular (Biológicas) Fac. de Ciencias Biológicas TRUE pub 2023-06-18T05:51:16Z 2023-06-18T05:51:16Z 2016 journal article https://hdl.handle.net/20.500.14352/23479 2045-2322 10.1038/srep38986 eng ORCHID (261378) Atribución 3.0 España https://creativecommons.org/licenses/by/3.0/es/ open access application/pdf Springer Nature