Cell Wall Stress Responses in Bacillus Subtilis: The Regulatory Network of the Bacitracin Stimulon

Mol Microbiol. 2003 Dec;50(5):1591-604. doi: 10.1046/j.1365-2958.2003.03786.x.

Abstract

In response to sublethal concentrations of antibiotics, bacteria often induce an adaptive response that can contribute to antibiotic resistance. We report the response of Bacillus subtilis to bacitracin, an inhibitor of cell wall biosynthesis found in its natural environment. Analysis of the global transcriptional profile of bacitracin-treated cells reveals a response orchestrated by two alternative sigma factors (sigmaB and sigmaM) and three two-component systems (YvqEC, YvcPQ and BceRS). All three two-component systems are located next to target genes that are strongly induced by bacitracin, and the corresponding histidine kinases share an unusual topology: they lack about 100 amino acids in their extracellular sensing domain, which is almost entirely buried in the cytoplasmic membrane. Sequence analysis indicates that this novel N-terminal sensing domain is a characteristic feature of a subfamily of histidine kinases, found almost entirely in Gram-positive bacteria and frequently linked to ABC transporters. A systematic mutational analysis of bacitracin-induced genes led to the identification of a new bacitracin-resistance determinant, bceAB, encoding a putative ABC transporter. The bcrC bacitracin resistance gene, which is under the dual control of sigmaX and sigmaM, was also induced by bacitracin. By comparing the bacitracin and the vancomycin stimulons, we can differentiate between loci induced specifically by bacitracin and those that are induced by multiple cell wall-active antibiotics.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Bacillus subtilis / drug effects*
  • Bacillus subtilis / genetics
  • Bacillus subtilis / growth & development
  • Bacillus subtilis / metabolism
  • Bacitracin / pharmacology*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Cell Wall / drug effects*
  • Cell Wall / metabolism
  • Drug Resistance, Bacterial
  • Gene Expression Profiling
  • Gene Expression Regulation, Bacterial
  • Heat-Shock Response / drug effects*
  • Histidine Kinase
  • Microbial Sensitivity Tests
  • Oligonucleotide Array Sequence Analysis
  • Protein Kinases / metabolism
  • Sigma Factor / genetics
  • Sigma Factor / metabolism
  • Signal Transduction
  • Vancomycin / pharmacology

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • SigB protein, Bacteria
  • Sigma Factor
  • Bacitracin
  • Vancomycin
  • Protein Kinases
  • Histidine Kinase