RbpA and σB association regulates polyphosphate levels to modulate mycobacterial isoniazid-tolerance

Academic Article

Abstract

  • To facilitate survival under drug stresses, a small population of Mycobacterium tuberculosis can tolerate bactericidal concentrations of drugs without genetic mutations. These drug-tolerant mycobacteria can be induced by environmental stresses and contribute to recalcitrant infections. However, mechanisms underlying the development of drug-tolerant mycobacteria remain obscure. Herein, we characterized a regulatory pathway which is important for the tolerance to isoniazid (INH) in Mycobacterium smegmatis. We found that the RNA polymerase binding protein RbpA associates with the stress response sigma factor σ , to activate the transcription of ppk1, the gene encoding polyphosphate kinase. Subsequently, intracellular levels of inorganic polyphosphate increase to promote INH-tolerant mycobacteria. Interestingly, σ and ppk1 expression varied proportionately in mycobacterial populations and positively correlated with tolerance to INH in individual mycobacteria. Moreover, sigB and ppk1 transcription are both induced upon nutrient depletion, a condition that stimulates the formation of INH-tolerant mycobacteria. Over-expression of ppk1 in rbpA knockdown or sigB deleted strains successfully restored the number of INH-tolerant mycobacteria under both normal growth and nutrient starved conditions. These data suggest that RbpA and σ regulate ppk1 expression to control drug tolerance both during the logarithmic growth phase and under the nutrition starved conditions. B B B
  • Authors

    Digital Object Identifier (doi)

    Author List

  • Wang Z; Cumming BM; Mao C; Zhu Y; Lu P; Steyn AJC; Chen S; Hu Y
  • Start Page

  • 627
  • End Page

  • 640
  • Volume

  • 108
  • Issue

  • 6