Cox, Jonathan A. G.Mugumbate, GraceVela González del Peral, LauraJankute, MonikaAbrahams, Katherine A.Jervis, PeterJackenkroll, StefanPérez, AranchaAlemparte, CarlosEsquivias, JorgeLelièvre, JoëlRamón Olayo, Fernando AntonioBarros, DavidBallell, LluisBesra, Gurdyal S.2023-06-182023-06-1820162045-232210.1038/srep38986https://hdl.handle.net/20.500.14352/23479High-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.engAtribución 3.0 Españahttps://creativecommons.org/licenses/by/3.0/es/journal articlehttps://www.nature.com/srep/open access579.873.21579.8Mycobacterium tuberculosis GuaB2phenotypic screenBiologíaBiología molecular (Biología)Microbiología (Biología)24 Ciencias de la Vida2415 Biología Molecular2414 Microbiología