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Beyond Inhibition: Sublethal Rifampicin-Induced Molecular Adaptations Confer Phenotypic Drug Tolerance in

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Summary

Sublethal rifampicin exposure primes tuberculosis bacteria for enhanced tolerance to lethal drug levels. This priming involves significant proteomic shifts, presenting a major challenge for effective tuberculosis treatment.

Keywords:
Mycobacterium smegmatisMycobacterium tuberculosismass spectrometryphenotypic toleranceproteomicssublethal rifampicin

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Area of Science:

  • Microbiology
  • Molecular Biology
  • Drug Resistance

Background:

  • Tuberculosis (TB) is a global health crisis driven by *Mycobacterium tuberculosis* (Mtb) resilience.
  • Sublethal antibiotic concentrations, due to nonadherence or poor drug penetration in granulomas, promote Mtb tolerance and resistance.
  • Mtb exhibits both phenotypic tolerance and genotypic resistance within host granulomas, complicating treatment.

Purpose of the Study:

  • To investigate if sublethal rifampicin functions as a signaling molecule in mycobacteria.
  • To determine if rifampicin exposure triggers phenotypic changes that enhance tolerance to lethal antibiotic concentrations.
  • To analyze proteomic alterations in *Mycobacterium smegmatis* (Msm) and *Mycobacterium tuberculosis* H37Ra upon sublethal rifampicin exposure.

Main Methods:

  • Exposure of Msm and Mtb H37Ra to half-MIC rifampicin.
  • Proteomic profiling using deep data-independent acquisition (DIA) mass spectrometry at early (45 min) and recovery (180 min) time points.
  • Analysis of differential protein expression and pathway dysregulation.

Main Results:

  • Msm developed phenotypic tolerance after sublethal rifampicin exposure, with initial growth deceleration followed by proliferation.
  • Early proteomic response in Msm included upregulation of ribosomal proteins, DNA replication, purine biosynthesis, and resistance-associated proteins.
  • Mtb H37Ra showed conserved adaptive responses and species-specific dysregulation of drug transport and cell envelope pathways.

Conclusions:

  • Sublethal rifampicin exposure primes mycobacteria to tolerate higher, lethal drug concentrations.
  • The observed proteomic shifts highlight a significant challenge in developing effective tuberculosis therapies.
  • Understanding these adaptive mechanisms is crucial for overcoming drug tolerance in TB treatment.