title: Genome-wide dynamics of a bacterial response to antibiotics that target the cell envelope.
abstract: BACKGROUND
  A decline in the discovery of new antibacterial drugs, coupled with a persistent rise in the occurrence of drug-resistant bacteria, has highlighted antibiotics as a diminishing resource. The future development of new drugs with novel antibacterial activities requires a detailed understanding of adaptive responses to existing compounds. This study uses Streptomyces coelicolor A3(2) as a model system to determine the genome-wide transcriptional response following exposure to three antibiotics (vancomycin, moenomycin A and bacitracin) that target distinct stages of cell wall biosynthesis.
  
  
  RESULTS
  A generalised response to all three antibiotics was identified which involves activation of transcription of the cell envelope stress sigma factor σ(E), together with elements of the stringent response, and of the heat, osmotic and oxidative stress regulons. Attenuation of this system by deletion of genes encoding the osmotic stress sigma factor σ(B) or the ppGpp synthetase RelA reduced resistance to both vancomycin and bacitracin. Many antibiotic-specific transcriptional changes were identified, representing cellular processes potentially important for tolerance to each antibiotic. Sensitivity studies using mutants constructed on the basis of the transcriptome profiling confirmed a role for several such genes in antibiotic resistance, validating the usefulness of the approach.
  
  
  CONCLUSIONS
  Antibiotic inhibition of bacterial cell wall biosynthesis induces both common and compound-specific transcriptional responses. Both can be exploited to increase antibiotic susceptibility. Regulatory networks known to govern responses to environmental and nutritional stresses are also at the core of the common antibiotic response, and likely help cells survive until any specific resistance mechanisms are fully functional.
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: Andy
authors.initials: A
authors.lastname: Hesketh
authors.forename: Chris
authors.initials: C
authors.lastname: Hill
authors.forename: Jehan
authors.initials: J
authors.lastname: Mokhtar
authors.forename: Gabriela
authors.initials: G
authors.lastname: Novotna
authors.forename: Ngat
authors.initials: N
authors.lastname: Tran
authors.forename: Mervyn
authors.initials: M
authors.lastname: Bibb
authors.forename: Hee-Jeon
authors.initials: HJ
authors.lastname: Hong
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology*; D001710:Biotin / Q000096:biosynthesis; D002473:Cell Wall / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000187:drug effects / Q000235:genetics; D016680:Genome, Bacterial / Q000235:genetics*; D018869:Heat-Shock Response / Q000187:drug effects / Q000235:genetics; D008025:Ligases / Q000096:biosynthesis; D009997:Osmotic Pressure / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010457:Peptidoglycan / Q000096:biosynthesis; D010458:Peptidyl Transferases / Q000235:genetics / Q000378:metabolism; D018085:Regulon / Q000235:genetics; D012808:Sigma Factor / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D048372:Streptomyces coelicolor / Q000166:cytology / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015032:Zinc / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000900:Anti-Bacterial Agents; D010457:Peptidoglycan; D012808:Sigma Factor; D001710:Biotin; D010458:Peptidyl Transferases; D008025:Ligases; C028812:guanosine 3',5'-polyphosphate synthetases; D015032:Zinc