Abstract
The diarylquinoline R207910 (TMC207) is a promising candidate in clinical development for the treatment of tuberculosis. Though R207910-resistant mycobacteria bear mutations in ATP synthase, the compound's precise target is not known. Here we establish by genetic, biochemical and binding assays that the oligomeric subunit c (AtpE) of ATP synthase is the target of R207910. Thus targeting energy metabolism is a new, promising approach for antibacterial drug discovery.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Synthetase Complexes / chemistry
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ATP Synthetase Complexes / drug effects
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ATP Synthetase Complexes / metabolism*
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Antitubercular Agents / pharmacology*
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Bacterial Proteins / chemistry
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Bacterial Proteins / drug effects
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Bacterial Proteins / metabolism
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Bacterial Proton-Translocating ATPases
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Binding Sites
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Diarylquinolines
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Electrophoresis, Gel, Two-Dimensional
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Kinetics
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Mycobacterium smegmatis / drug effects
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Mycobacterium smegmatis / enzymology
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Protein Subunits / drug effects
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Protein Subunits / isolation & purification
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Protein Subunits / metabolism
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Quinolines / pharmacology*
Substances
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Antitubercular Agents
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Bacterial Proteins
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Diarylquinolines
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Protein Subunits
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Quinolines
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bedaquiline
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ATP Synthetase Complexes
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ATP synthase subunit C, Mycobacterium tuberculosis
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Bacterial Proton-Translocating ATPases
Associated data
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PubChem-Substance/24429254
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PubChem-Substance/24429255
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PubChem-Substance/24429256
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PubChem-Substance/24429257
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PubChem-Substance/24429258
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PubChem-Substance/24429259
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PubChem-Substance/24429260
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PubChem-Substance/24429261
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PubChem-Substance/24429262
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PubChem-Substance/24429263