Estrés oxidativo del huésped prepara a las micobacterias para una rápida evolución de la resistencia a los...

Área de la Ciencia:

• Microbiology
• Genetics
• Drug Resistance

Sus antecedentes:

• Multidrug-resistant Mycobacterium tuberculosis (Mtb) poses a significant threat to global tuberculosis control.
• Mechanisms driving rapid drug resistance evolution in Mtb are not fully understood.
• Existing paradigms suggest resistance mutations precede compensatory adaptations.

Objetivo del estudio:

• To investigate how pre-existing mutations in oxidative stress response genes influence the evolution of isoniazid resistance in Mtb.
• To challenge the traditional view of resistance and compensatory adaptation sequencing.
• To explore the role of host-imposed oxidative stress in accelerating Mtb drug resistance.

Principales métodos:

• Utilized Mycobacterium smegmatis mc^2 155 (Msm) as a model organism.
• Exposed Msm to sublethal isoniazid (INH) concentrations to select for low-level resistance and tolerance (LLRT) mutants.
• Analyzed clinical Mtb isolates using Bayesian methods and reanalyzed genome-wide CRISPRi screens.

Principales resultados:

• Loss-of-function mutations in oxidative stress response regulator (ohrR) accelerated high-level INH resistance.
• Sublethal oxidative stress significantly increased the rate of INH resistance evolution in Msm.
• Mutations in oxidative stress response genes were strongly associated with INH-resistant Mtb strains in clinical isolates.

Conclusiones:

• Pre-existing mutations in oxidative stress genes create permissive backgrounds for rapid, cost-free resistance evolution.
• Host oxidative stress and poor drug penetration may synergistically promote Mtb resistance.
• Targeting oxidative stress defenses could be a strategy to mitigate the emergence of antibiotic resistance in tuberculosis.