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The polyketide synthase-associated multidrug tolerance in Mycobacterium intracellulare clinical isolates

Isamu Matsunaga1, Shinji Maeda, Shinji Meda

  • 1Laboratory of Cell Regulation, Institute for Virus Research, Kyoto University, Kyoto, Japan. i_matsun@virus.kyoto-u.ac.jp

Chemotherapy
|November 23, 2012
PubMed
Abstract

Insights

Polyketide synthase Pks12 (Pks12) contributes to multidrug resistance in Mycobacterium avium-intracellulare complex. Disrupting Pks12 increases intracellular drug accumulation, suggesting a novel therapeutic target for treating resistant infections.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Drug Resistance Research

Background:

  • Intrinsic multidrug resistance in Mycobacterium avium-intracellulare complex complicates treatment.
  • Previous studies indicated that deleting polyketide synthase Pks12 in M. avium reduces intrinsic resistance.

Purpose of the Study:

  • To investigate the role of Pks12 in drug resistance in M. intracellulare clinical isolates.
  • To explore the mechanism of Pks12-mediated drug resistance, focusing on intracellular drug accumulation.

Main Methods:

  • Examined Pks12 expression and activity in 9 M. intracellulare clinical isolates.
  • Assessed drug susceptibilities to four antibiotics.
  • Created pks12-disrupted M. bovis bacillus Calmette-Guérin (BCG) mutants and complemented strains.
  • Measured intracellular ethidium bromide (EtBr) accumulation in M. intracellulare and BCG strains.

Main Results:

  • A positive correlation was observed between Pks12 and resistance to all tested antibiotics.
  • Drug-susceptible M. intracellulare strains exhibited higher intracellular EtBr accumulation.
  • Pks12-disrupted BCG strains showed significantly greater EtBr accumulation compared to wild-type and complemented strains.

Conclusions:

  • Pks12 plays a role in controlling multidrug resistance in M. intracellulare.
  • Intracellular drug accumulation is a key mechanism influenced by Pks12.
  • Targeting Pks12 may offer a strategy to overcome multidrug resistance in mycobacterial infections.

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