Emergence of vancomycin tolerance in Streptococcus pneumoniae

R. Novak, B. Henriques, E. Charpentier, S. Normark and E. Tuomanen ()
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R. Novak: Dept of Infectious Diseases, St. Jude Children's Research Hospital
B. Henriques: Swedish Institute for Infectious Disease Control, Karolinska Institute
E. Charpentier: Dept of Infectious Diseases, St. Jude Children's Research Hospital
S. Normark: Swedish Institute for Infectious Disease Control, Karolinska Institute
E. Tuomanen: Dept of Infectious Diseases, St. Jude Children's Research Hospital

Nature, 1999, vol. 399, issue 6736, 590-593

Abstract: Abstract Streptococcus pneumoniae, the pneumococcus, is the most common cause of sepsis and meningitis1. Multiple-antibiotic-resistant strains are widespread, and vancomycin is the antibiotic of last resort2,3. 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 resistance4. 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.

Date: 1999
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DOI: 10.1038/21202

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