1. Turning the respiratory flexibility of Mycobacterium tuberculosis against itself.
- Author
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Lamprecht DA, Finin PM, Rahman MA, Cumming BM, Russell SL, Jonnala SR, Adamson JH, and Steyn AJ
- Subjects
- Adenosine Triphosphate metabolism, Animals, Antitubercular Agents therapeutic use, Clofazimine pharmacology, Clofazimine therapeutic use, Diarylquinolines pharmacology, Diarylquinolines therapeutic use, Drug Therapy, Combination methods, Hep G2 Cells, Humans, Imidazoles chemical synthesis, Imidazoles pharmacology, Imidazoles therapeutic use, Inhibitory Concentration 50, Macrophages microbiology, Mice, Mutation, Mycobacterium tuberculosis drug effects, Piperidines chemical synthesis, Piperidines pharmacology, Piperidines therapeutic use, Pyridines chemical synthesis, Pyridines pharmacology, Pyridines therapeutic use, RAW 264.7 Cells, Tuberculosis, Multidrug-Resistant microbiology, Antitubercular Agents pharmacology, Electron Transport Chain Complex Proteins antagonists & inhibitors, Mycobacterium tuberculosis physiology, Reactive Oxygen Species metabolism, Tuberculosis, Multidrug-Resistant drug therapy
- 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.
- Published
- 2016
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