Journal
FRONTIERS IN PHARMACOLOGY
Volume 8, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2017.00681
Keywords
Mycobacterium tuberculosis; phenotypic hits; target identification; drug resistance; EthR; InhA
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Funding
- EMBL Interdisciplinary Postdoc (EIPOD) programme under Marie Sklodowska-Curie Actions COFUND [291772]
- Foundation for the National Institutes of Health (NIH) [OPP1024021]
- Foundation for the National Institutes of Health (FNIH) [OPP1158806]
- European Community's Seventh Framework Programme [260872]
- Wellcome Trust
- European Molecular Biology Laboratory
- nation states of the European Molecular Biology Laboratory
- Wellcome Trust [200814/Z/16/Z]
- MRC [MR/M026302/1, MR/N501864/1] Funding Source: UKRI
- Medical Research Council [MR/M026302/1, MR/N501864/1] Funding Source: researchfish
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Mycobacterium phenotypic hits are a good reservoir for new chemotypes for the treatment of tuberculosis. However, the absence of defined molecular targets and modes of action could lead to failure in drug development. Therefore, a combination of ligand-based and structure-based chemogenomic approaches followed by biophysical and biochemical validation have been used to identify targets for Mycobacterium tuberculosis phenotypic hits. Our approach identified EthR and InhA as targets for several hits, with some showing dual activity against these proteins. From the 35 predicted EthR inhibitors, eight ewxhibited an IC50 below 50 mu M against M. tuberculosis EthR and three were confirmed to be also simultaneously active against InhA. Further hit validation was performed using X-ray crystallography yielding eight new crystal structures of EthR inhibitors. Although the EthR inhibitors attain their activity against M. tuberculosis by hitting yet undefined targets, these results provide new lead compounds that could be further developed to be used to potentiate the effect of EthA activated pro-drugs, such as ethionamide, thus enhancing their bactericidal effect.
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