A complex regulatory network controlling intrinsic multidrug resistance in Mycobacterium smegmatis

Mol Microbiol. 2014 Jan;91(1):121-34. doi: 10.1111/mmi.12448. Epub 2013 Nov 27.

Abstract

Mycobacteria are intrinsically resistant to a variety of stresses including many antibiotics. Although a number of pathways have been described to account for the observed resistances, the mechanisms that control the expression of genes required in these processes remain poorly defined. Here we report the role of a predicted anti-sigma factor, MSMEG_6129 and a predicted eukaryotic like serine/threonine protein kinase, MSMEG_5437, in the intrinsic resistance of Mycobacterium smegmatis to a variety of stresses including the genotoxic agent mitomycin C, hydrogen peroxide and at least four different antibiotics - isoniazid, chloramphenicol, erythromycin and tetracycline. We show that MSMEG_5437 influences the phosphorylation state of MSMEG_6129. Further, MSMEG_6129 controls the expression of a plethora of genes including efflux pumps, ABC transporters, catalases and transcription factors, either directly or via regulators like WhiB7, which account for the observed multi-drug resistance phenotypes. MSMEG_6129 in turn phosphorylates a contiguously located putative anti-anti-sigma factor, MSMEG_6127. We therefore propose that MSMEG_5437, MSMEG_6129 and MSMEG_6127 are components of a master regulatory network, upstream of whiB7, that controls the activity of one or more of the 28 sigma factors in M. smegmatis. Together, this network controls the expression of a regulon required for resistance to several unrelated antibiotics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Catalase / metabolism
  • Drug Resistance, Multiple, Bacterial / genetics*
  • Gene Expression Regulation, Bacterial
  • Gene Regulatory Networks*
  • Hydrogen Peroxide / pharmacology
  • Mitomycin / pharmacology
  • Mycobacterium smegmatis / drug effects*
  • Mycobacterium smegmatis / genetics
  • Mycobacterium smegmatis / metabolism*
  • Phenotype
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Regulon*
  • Sequence Alignment
  • Sigma Factor / genetics
  • Sigma Factor / metabolism*
  • Transcription Factors / metabolism

Substances

  • ATP-Binding Cassette Transporters
  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Sigma Factor
  • Transcription Factors
  • Mitomycin
  • Hydrogen Peroxide
  • Catalase
  • Protein-Serine-Threonine Kinases