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Turning the respiratory flexibility of Mycobacterium tuberculosis against itself.

Turning the respiratory flexibility of Mycobacterium tuberculosis against itself.
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Lamprecht DA, Finin PM, Rahman MA, Cumming BM, Russell SL, Jonnala SR, Adamson JH, Steyn AJ,


Lamprecht DA, Finin PM, Rahman MA, Cumming BM, Russell SL, Jonnala SR, Adamson JH, Steyn AJ, (click to view)

Lamprecht DA, Finin PM, Rahman MA, Cumming BM, Russell SL, Jonnala SR, Adamson JH, Steyn AJ,

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Nature communications 2016 08 107() 12393 doi 10.1038/ncomms12393

Abstract

The Mycobacterium tuberculosis (Mtb) electron transport chain (ETC) has received significant attention as a drug target, however its vulnerability may be affected by its flexibility in response to disruption. Here we determine the effect of the ETC inhibitors bedaquiline, Q203 and clofazimine on the Mtb ETC, and the value of the ETC as a drug target, by measuring Mtb’s respiration using extracellular flux technology. We find that Mtb’s ETC rapidly reroutes around inhibition by these drugs and increases total respiration to maintain ATP levels. Rerouting is possible because Mtb rapidly switches between terminal oxidases, and, unlike eukaryotes, is not susceptible to back pressure. Increased ETC activity potentiates clofazimine’s production of reactive oxygen species, causing rapid killing in vitro and in a macrophage model. Our results indicate that combination therapy targeting the ETC can be exploited to enhance killing of Mtb.

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