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The pH gradient contributes to persistence in Mycobacterium tuberculosis.

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Drug-tolerant tuberculosis (TB) persister cells are hard to eliminate. Researchers found niclosamide (NCA) induces TB drug tolerance by disrupting the pH gradient, offering a new tool to study persister cells.

Keywords:
Drug toleranceIntracellular pHMembrane potentialNiclosamidePMFPersistersTB

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Area of Science:

  • Microbiology
  • Drug Discovery
  • Molecular Biology

Background:

  • Tuberculosis (TB) treatment is challenging due to drug-tolerant persister cells of *Mycobacterium tuberculosis* (Mtb).
  • These persister cells survive antibiotics without genetic resistance, complicating eradication efforts.

Purpose of the Study:

  • To identify FDA-approved drugs targeting TB persister cells.
  • To investigate the mechanism by which niclosamide (NCA) affects Mtb drug tolerance.

Main Methods:

  • Screened 2,336 FDA-approved drugs for compounds affecting Mtb persistence.
  • Investigated the role of pH gradient and membrane potential in NCA-induced tolerance.
  • Performed transcriptomic analysis and gene knockdowns to identify key genes.

Main Results:

  • Niclosamide (NCA), an antiparasitic, was identified as a potent inducer of drug tolerance in Mtb.
  • NCA protected Mtb from standard TB drugs by disrupting the pH gradient and causing intracellular acidification.
  • Specific genes involved in promoting or mitigating this chemically-induced persister (CIP) phenotype were identified.

Conclusions:

  • Disruption of the pH gradient is a key mechanism for inducing drug tolerance in Mtb.
  • NCA serves as a tool to rapidly induce and study drug tolerance in TB.
  • This research provides insights into persister cell biology for TB and other infectious diseases.