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.
Grupo de Bibliometría, Evaluación de Evidencia y Revisiones Sistemáticas (BEERS), Human Medicine Career, Universidad Científica del Sur, Lima, Peru, South America.
Background: Mycobacterium tuberculosis (M. tuberculosis) is an infectious disease that remains a significant global health problem. Despite efforts to reduce the disease, the disease remains prevalent in many parts of the world.
Mycobacterium tuberculosis causes human tuberculosis. As mycobacteria are protected by thick lipid cell wall, humans have developed immune responses against diverse mycobacterial lipids. Most of these immunostimulatory lipids are known as adjuvants acting through innate immune receptors, such as C-type lectin receptors.
The world's leading infectious disease killer tuberculosis (TB) has >10 million new cases and ~1.5 million mortalities yearly. Effective TB control and management depends on accurate and timely diagnosis to improve treatment, curb transmission and reduce the burden on the medical system.
Tuberculosis is a transmissible disease caused by the bacterium . It is the leading cause of mortality due to infectious diseases. Tuberculous pericarditis is one of the manifestations of extrapulmonary tuberculosis and represents the primary cause of pericardial effusion in developing countries.
