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Emergence of vancomycin tolerance in Streptococcus pneumoniae

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.

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Figure 1: Effect of loss of function of vncR and vncS on bactericidal activity of vancomycin.
Figure 2: Interrelationships of VncR and VncS.
Figure 3: Functional assay of autolytic activity.

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Acknowledgements

This work was supported in part by grants from the NIH (to E.T.), the Cancer Center CORE Grant and the American Lebanese Syrian Associated Charities and åke Wiberg Foundation. We thank J. S. Braun for help with the animal model, J. Li for technical assistance and P. Murray for helpful suggestions and discussions.

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Correspondence to E. Tuomanen.

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Novak, R., Henriques, B., Charpentier, E. et al. Emergence of vancomycin tolerance in Streptococcus pneumoniae. Nature 399, 590–593 (1999). https://doi.org/10.1038/21202

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