Universidad Complutense de Madrid
E-Prints Complutense

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

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Cox, Jonathan A. G. y Mugumbate, Grace y Vela González del Peral, Laura y Jankute, Monika y A. Abrahams, Katherine y Jervis, Peter y Jackenkroll, Stefan y Pérez, Arancha y Alemparte, Carlos y Esquivias, Jorge y Lelièvre, Joël y Ramón Olayo, Fernando Antonio y Barros, David y Ballell, Lluis y S. Besra, Gurdyal (2016) Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen. Scientific Reports, 6 (38986). ISSN 2045-2322

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URL Oficial: https://www.nature.com/srep/



Resumen

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.


Tipo de documento:Artículo
Palabras clave:Mycobacterium tuberculosis GuaB2; phenotypic screen
Materias:Ciencias Biomédicas > Biología
Ciencias Biomédicas > Biología > Biología molecular
Ciencias Biomédicas > Biología > Microbiología
Código ID:46387
Depositado:08 Feb 2018 17:14
Última Modificación:09 Feb 2018 09:47

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