Noise in a metabolic pathway leads to persister formation in Mycobacterium tuberculosis

Abstract

Tuberculosis is difficult to treat due to dormant cells in hypoxic granulomas, and stochastically-formed persisters tolerant of antibiotics. Bactericidal antibiotics kill by corrupting their energy-dependent targets. We reasoned that noise in the expression of an energy-generating component will produce rare persister cells. In sorted low ATP M. tuberculosis grown on acetate there is considerable cell-to-cell variation in the level of mRNA coding for AckA, the acetate kinase. Quenching the noise by overexpressing ackA sharply decreases persisters, showing that it acts as the main persister gene under these conditions. This demonstrates that a low energy mechanism is responsible for the formation of M. tuberculosis persisters and suggests that the mechanism of their antibiotic tolerance is similar to that of dormant cells in a granuloma. Entrance into a low energy state driven by stochastic variation in expression of energy-producing enzymes is likely a general mechanism by which bacteria produce persisters.

Bacterial survivors: evaluating the mechanisms of antibiotic persistence

“…In Mycobacteria, the stress response pathway involving the σ factor SigE is characterized by a bimodal expression of the stringent response modulator Rel, resulting in a subpopulation with a high Rel translation (H-state) [174,175], and since SigE has also been implicated in persister formation [176], the H-state might represent persistence, although this speculation has not been validated. Additionally, it was recently reported that stochasticity associated with acetate kinase essential for acetate to enter the Krebs cycle mediates persistence in M. tuberculosis [177]. In Bacillus subtillis, the noise-driven ComKS system regulates competence and growth arrest, imposing a triggered persistence [178].…”