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Nat Commun. 2016 Aug 10;7:12393. doi: 10.1038/ncomms12393.

Turning the respiratory flexibility of Mycobacterium tuberculosis against itself.

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KwaZulu Natal Research Institute for Tuberculosis and HIV (K-RITH), K-RITH Tower Building Level 3, 719 Umbilo Road, Durban 4001, South Africa.
Department of Internal Medicine, University of Pittsburgh, 1218 Scaife Hall 3550 Terrace Street, Pittsburgh, Pennsylvania 15261, USA.
Tuberculosis Research Section, NIAID, NIH, 6610 Rockledge Drive, Bethesda, Maryland 20817, USA.
Department of Microbiology, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, Alabama 35294-2170, USA.
Centres for AIDS Research and Free Radical Biology, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, Alabama 35294-2170, USA.


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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