Open AccessTurning the respiratory flexibility of Mycobacterium tuberculosis against itself
Author(s) -
Dirk A. Lamprecht,
Peter M. Finin,
Md. Aejazur Rahman,
Bridgette M. Cumming,
Sarah Russell,
Surendranadha Reddy Jonnala,
John Adamson,
Adrie J. C. Steyn
Publication year - 2016
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/ncomms12393
Subject(s) - bedaquiline , clofazimine , mycobacterium tuberculosis , flexibility (engineering) , tuberculosis , extracellular , drug , microbiology and biotechnology , respiration , respiratory chain , biology , chemistry , mitochondrion , pharmacology , medicine , immunology , leprosy , statistics , botany , mathematics , pathology
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.