title: Turning the respiratory flexibility of Mycobacterium tuberculosis against itself.
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.
authors: KwaZulu Natal Research Institute for Tuberculosis and HIV (K-RITH), K-RITH Tower Building Level 3, 719 Umbilo Road, Durban 4001, South Africa.
authors: Dirk A
authors: DA
authors: Lamprecht
authors: 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.
authors: Peter M
authors: PM
authors: Finin
authors: KwaZulu Natal Research Institute for Tuberculosis and HIV (K-RITH), K-RITH Tower Building Level 3, 719 Umbilo Road, Durban 4001, South Africa.
authors: Md Aejazur
authors: MA
authors: Rahman
authors: KwaZulu Natal Research Institute for Tuberculosis and HIV (K-RITH), K-RITH Tower Building Level 3, 719 Umbilo Road, Durban 4001, South Africa.
authors: Bridgette M
authors: BM
authors: Cumming
authors: KwaZulu Natal Research Institute for Tuberculosis and HIV (K-RITH), K-RITH Tower Building Level 3, 719 Umbilo Road, Durban 4001, South Africa.
authors: Shannon L
authors: SL
authors: Russell
authors: Tuberculosis Research Section, NIAID, NIH, 6610 Rockledge Drive, Bethesda, Maryland 20817, USA.
authors: Surendranadha R
authors: SR
authors: Jonnala
authors: KwaZulu Natal Research Institute for Tuberculosis and HIV (K-RITH), K-RITH Tower Building Level 3, 719 Umbilo Road, Durban 4001, South Africa.
authors: John H
authors: JH
authors: Adamson
authors: 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 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.
authors: Adrie J C
authors: AJ
authors: Steyn
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002991:Clofazimine / Q000494:pharmacology / Q000627:therapeutic use; D064687:Diarylquinolines / Q000494:pharmacology / Q000627:therapeutic use; D004359:Drug Therapy, Combination / Q000379:methods; D045222:Electron Transport Chain Complex Proteins / Q000037:antagonists & inhibitors*; D056945:Hep G2 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000502:physiology*; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D000067996:RAW 264.7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; D045222:Electron Transport Chain Complex Proteins; D007093:Imidazoles; D010880:Piperidines; D011725:Pyridines; D017382:Reactive Oxygen Species; C584497:telacebec; C493870:bedaquiline; D000255:Adenosine Triphosphate; D002991:Clofazimine