Journal article
Whole Cell Target Engagement Identifies Novel Inhibitors of Mycobacterium tuberculosis Decaprenylphosphoryl-β-d-ribose Oxidase.
- Batt SM School of Biosciences, University of Birmingham , Birmingham B15 2TT, United Kingdom.
- Cacho Izquierdo M School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL) , CH-1015 Lausanne, Switzerland.
- Castro Pichel J School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL) , CH-1015 Lausanne, Switzerland.
- Stubbs CJ School of Biosciences, University of Birmingham , Birmingham B15 2TT, United Kingdom.
- Vela-Glez Del Peral L
- Pérez-Herrán E
- Dhar N
- Mouzon B
- Rees M
- Hutchinson JP
- Young RJ
- McKinney JD
- Barros Aguirre D
- Ballell L
- Besra GS
- Argyrou A
- 2016-09-14
Published in:
- ACS infectious diseases. - 2015
English
We have targeted the Mycobacterium tuberculosis decaprenylphosphoryl-β-d-ribose oxidase (Mt-DprE1) for potential chemotherapeutic intervention of tuberculosis. A multicopy suppression strategy that overexpressed Mt-DprE1 in M. bovis BCG was used to profile the publically available GlaxoSmithKline antimycobacterial compound set, and one compound (GSK710) was identified that showed an 8-fold higher minimum inhibitory concentration relative to the control strain. Analogues of GSK710 show a clear relationship between whole cell potency and in vitro activity using an enzymatic assay employing recombinant Mt-DprE1, with binding affinity measured by fluorescence quenching of the flavin cofactor of the enzyme. M. bovis BCG spontaneous resistant mutants to GSK710 and a closely related analogue were isolated and sequencing of ten such mutants revealed a single point mutation at two sites, E221Q or G248S within DprE1, providing further evidence that DprE1 is the main target of these compounds. Finally, time-lapse microscopy experiments showed that exposure of M. tuberculosis to a compound of this series arrests bacterial growth rapidly followed by a slower cytolysis phase.
- Language
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- English
- Open access status
- closed
- Identifiers
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- DOI 10.1021/acsinfecdis.5b00065
- PMID 27623058
- Persistent URL
- https://sonar.ch/global/documents/80029
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