Regulatory Mechanisms in Mycobacterial Dormancy

Mycobacterial species such as Mycobacterium tuberculosis and Mycobacterium abscessus employ intricate regulatory networks to enter and maintain a dormant state when faced with hostile host environments. Central to this process is the ability to sense and respond to hypoxia, nitric oxide and other stress signals via two-component regulatory systems that activate a suite of genes collectively known as the dormancy regulon. Transcriptional regulators detect gas ligands or redox changes and orchestrate global shifts in metabolism, cell‐wall composition and energy conservation. Post-translational modifications, including acetylation of key regulators, further fine-tune DNA-binding affinities and the kinetics of regulon induction. In parallel, toxin–antitoxin modules contribute to persister cell formation by modulating translation and growth arrest. Together, these layers of control enable mycobacteria to withstand prolonged nutrient limitation, antimicrobial pressure and immune attack, fuelling latent infection and complicating eradication efforts.

Research from Nature Portfolio

A quantitative proteomic investigation of Mycobacterium smegmatis exposed to sub-lethal rifampicin revealed that early adaptive responses engage multiple two-component systems, including MprA/MprB, before down-regulating the DosR regulon and up-regulating transcriptional and translational machinery. Temporal profiles showed coordinated dysregulation of heme and iron-scavenging pathways and a gradual increase in antibiotic inactivation enzymes. This study underscores how perturbation of antibiotic targets can drive a broad stress response that transiently mimics dormancy-associated programmes, highlighting potential vulnerabilities in signalling networks that could be exploited to prevent the emergence of drug-tolerant subpopulations.

Regulatory Mechanisms in Mycobacterial Dormancy publication trend

The graph below shows the total number of articles in regulatory mechanisms in mycobacterial dormancy across all publications each year (not limited to Nature Index journals).

Technical terms

Two-component regulatory system: A signalling circuit comprising a sensor kinase and a response regulator that transmits environmental signals into specific gene-expression changes.

Dormancy regulon: A defined set of genes coordinately induced under stress conditions to promote metabolic downshift and long-term survival.

Hypoxia: A state of low oxygen tension that triggers adaptive responses in mycobacteria, leading to non-replicating persistence.

Post-translational modification: A chemical alteration of a protein after its synthesis, such as phosphorylation or acetylation, that modulates its activity or interactions.

Toxin–antitoxin system: A genetic module encoding a stable toxin and a labile antitoxin, which together regulate bacterial growth and persistence under stress.

References

1. Mycobacterium abscessus DosRS two-component system controls a species-specific regulon required for adaptation to hypoxia. Frontiers in Cellular and Infection Microbiology (2023).
2. HigA2 (Rv2021c) Is a Transcriptional Regulator with Multiple Regulatory Targets in Mycobacterium tuberculosis. Microorganisms (2024).
3. A temporal proteome dynamics study reveals the molecular basis of induced phenotypic resistance in Mycobacterium smegmatis at sub-lethal rifampicin concentrations. Scientific Reports (2017).
4. Lysine acetylation of DosR regulates the hypoxia response of Mycobacterium tuberculosis. Emerging Microbes & Infections (2018).