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Role of DNA Double-Strand Break Formation in Gyrase Inhibitor-Mediated Killing of Nonreplicating Persistent

Priyanka Ashwath1, Paulina Osiecki1, Danielle Weiner2,3

  • 1Center for Discovery and Innovation, Hackensack Meridian Health, 111 Ideation Way, Nutley, New Jersey 07110, United States.

ACS Infectious Diseases
|September 24, 2024
PubMed

Insights

Fluoroquinolones kill nonreplicating tuberculosis bacteria in lesions by forming DNA double-strand breaks, unlike other gyrase inhibitors. This finding aids in developing better tuberculosis treatments.

Area of Science:

  • Microbiology
  • Infectious Diseases
  • Pharmacology

Background:

  • Tuberculosis (TB) remains a leading global infectious cause of death.
  • Nonreplicating Mycobacterium tuberculosis in caseum lesions are drug-tolerant, hindering TB cures.
  • Fluoroquinolones effectively target these persistent bacteria and sterilize TB lesions.

Purpose of the Study:

  • To investigate the efficacy of various gyrase inhibitors against Mycobacterium tuberculosis in different replicative states.
  • To compare the activity of fluoroquinolones with other gyrase inhibitors against persistent M. tuberculosis.
  • To elucidate the mechanism of action for bactericidal activity against nonreplicating M. tuberculosis.

Main Methods:

  • Assessed potency of multiple gyrase inhibitor classes against M. tuberculosis in various replication states.
  • Evaluated bactericidal activity against M. tuberculosis in ex vivo rabbit caseum.
  • Measured M. tuberculosis DNA gyrase supercoiling activity.
  • Determined the ability of inhibitors to induce DNA double-strand breaks.

Main Results:

  • Many gyrase inhibitors showed negligible activity against M. tuberculosis in caseum, unlike fluoroquinolones.
  • While other inhibitors affected supercoiling, only fluoroquinolones cleaved double-stranded DNA at low micromolar concentrations.
  • Fluoroquinolones demonstrated unique double-strand DNA cleavage activity.

Conclusions:

  • Fluoroquinolones' ability to induce double-strand breaks may drive their potent bactericidal effect against nonreplicating M. tuberculosis.
  • This mechanism is crucial for sterilizing lesions caused by persistent mycobacterial infections.
  • Findings inform the development of novel chemotherapeutic strategies for TB.
Keywords:
Mycobacterium tuberculosiscaseumdouble-strand breakfluoroquinolonesnonreplicating persistence

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