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Vancomycin Tolerance Induced by Erythromycin but Not by Loss of vncRS, vex3, or pep27 Function in Streptococcus pneumoniae. Gregory T. Robertson, 2002.Vancomycin-tolerant Streptococcus pneumoniae is a growing problem among drug-resistant human pathogens . Some vancomycin-tolerant pneumococci have been reported to carry mutations in loci encoding a two-component regulatory system designated VncRS or in a proximal ABC transporter, Vex . A model was advanced proposing that the tolerance phenotype resulted from the inability of a vncS mutant to respond to the Vex-transported Pep27 "death peptide" signal and dephosphorylate VncR, thereby preventing relief of repression of autolytic and other cell death functions in response to antibiotics . To explore this hypothesis, we constructed mutations in vncS, vncR, vex3, and pep27 in S . pneumoniae strain R6 and two additional genetic backgrounds . The lytic responses of the isogenic  vncS,
vex3,
vncR, and
pep27 mutants, but not a
lytA strain, to vancomycin were indistinguishable from that of the parent strain .
vncS strains also failed to exhibit tolerance to vancomycin at various doses in multiple media and showed wild-type sensitivity to other classes of autolysis-inducing antibiotics . In contrast, addition of subinhibitory levels of the antibiotic erythromycin led to tolerance to vancomycin during late, but not early, exponential-phase growth in a
vncS strain, in the parent strain R6, and in two other strains bearing erythromycin resistance markers, namely, a
vncR strain and an unrelated
comD strain that is defective in competence-quorum sensing . Thus, this tolerance effect resulted from changes in cell growth or other erythromycin-dependent phenomena and not inactivation of vncS per se . Consistent with these results, and in contrast to a previous report, we found that a synthetic form of Pep27 did not elicit lytic or nonlytic killing of pneumococci . Finally, microarray transcriptional analysis and ß-galactosidase reporter assays revealed VncS-dependent regulation of the vex123 gene cluster but did not support a role for VncRS in the regulation of autolytic or other putative cell death loci . Based on these findings, we propose that vancomycin tolerance in S . pneumoniae does not result from loss of vncS function alone .
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