New insights into the survival mechanisms of rifampicin-resistant Mycobacterium tuberculosis

Abstract

Objectives: Rifampicin is considered the most important antibiotic for treating TB, but unfortunately Mycobacterium tuberculosis is rapidly developing resistance to this drug. Despite the fervent research efforts to date, TB is still a major global problem, and hence new approaches are necessary to better characterize this disease, especially the mechanisms relating to drug resistance. Methods: Using a two-dimensional GC-coupled time-of-flight MS metabolomics approach, the most important metabolite markers characterizing rifampicin-resistant M. tuberculosis were identified. Results: The metabolite markers identified indicate instability in rifampicin-resistant M. tuberculosis mRNA, induced by the rpoB mutation. This results in a total depletion of aconitic acid, due to a shift in aconitase functionality towards mRNA binding and stability, and away from energy production and growth, and a subsequent increased dependency on alternative energy sources, fatty acids in particular. A number of other metabolic changes were observed, confirming an additional survival response for maintaining/remodelling the cell wall. Conclusions: This study shows the value of a metabolomics approach to biological investigations in a quest to better understand disease-causing organisms and their tolerance to existing medications, which would in the future undoubtedly assist in the development of alternative treatment approaches