title: Emergence of vancomycin tolerance in Streptococcus pneumoniae.
abstract: Streptococcus pneumoniae, the pneumococcus, is the most common cause of sepsis and meningitis. Multiple-antibiotic-resistant strains are widespread, and vancomycin is the antibiotic of last resort. Emergence of vancomycin resistance in this community-acquired bacterium would be catastrophic. Antibiotic tolerance, the ability of bacteria to survive but not grow in the presence of antibiotics, is a precursor phenotype to resistance. Here we show that loss of function of the VncS histidine kinase of a two-component sensor-regulator system in S. pneumoniae produced tolerance to vancomycin and other classes of antibiotic. Bacterial two-component systems monitor environmental parameters through a sensor histidine-kinase/phosphatase, which phosphorylates/dephosphorylates a response regulator that in turn mediates changes in gene expression. These results indicate that signal transduction is critical for the bactericidal activity of antibiotics. Experimental meningitis caused by the vncS mutant failed to respond to vancomycin. Clinical isolates tolerant to vancomycin were identified and DNA sequencing revealed nucleotide alterations in vncS. We conclude that broad antibiotic tolerance of S. pneumoniae has emerged in the community by a molecular mechanism that eliminates sensitivity to the current cornerstone of therapy, vancomycin.
authors.affiliation: Dept of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: R
authors.initials: R
authors.lastname: Novak
authors.forename: B
authors.initials: B
authors.lastname: Henriques
authors.forename: E
authors.initials: E
authors.lastname: Charpentier
authors.forename: S
authors.initials: S
authors.lastname: Normark
authors.forename: E
authors.initials: E
authors.lastname: Tuomanen
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins; D004352:Drug Resistance, Microbial / Q000235:genetics / Q000502:physiology; D005798:Genes, Bacterial; D016920:Meningitis, Bacterial / Q000188:drug therapy / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010403:Penicillin Resistance; D010766:Phosphorylation; D011008:Pneumococcal Infections / Q000188:drug therapy / Q000382:microbiology; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D011817:Rabbits; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014169:Transformation, Bacterial; D014640:Vancomycin / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D014157:Transcription Factors; C119633:VncR protein, Streptococcus pneumoniae; D014640:Vancomycin; D011494:Protein Kinases; C119671:VncS histidine kinase