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- W2973143352 abstract "Significance Drug combinations are an important strategy to increase treatment efficacy, reduce drug toxicity, and suppress drug resistance. Their development, however, is often empirical. Here, we report how the secondary consequences of the drug–target interaction (mode of action) can inform the development of rational mechanism-based combinations. We focus on bedaquiline (BDQ), the newest tuberculosis drug, because of known toxicities and emerging reports of resistance. We demonstrate that in addition to inhibiting its primary target, ATP synthase, BDQ causes a secondary inhibition of glutamine biosynthesis that is not directly antimycobacterial but renders Mycobacterium tuberculosis hypersensitive to inhibitors of its glutamine synthetase. These studies reveal drug-induced fitness costs as a specific and potentially valuable, but underappreciated, window to rational, mechanism-based drug combinations." @default.
- W2973143352 created "2019-09-19" @default.
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- W2973143352 date "2019-09-09" @default.
- W2973143352 modified "2023-10-15" @default.
- W2973143352 title "Mode-of-action profiling reveals glutamine synthetase as a collateral metabolic vulnerability of <i>M. tuberculosis</i> to bedaquiline" @default.
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- W2973143352 doi "https://doi.org/10.1073/pnas.1907946116" @default.
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