Transcription of the and glycopeptide resistance gene clusters is regulated by the VanRS and VanRS two-component regulatory systems, respectively. Histidine to glutamine substitutions were introduced at positions 164 of VanS and 233 of VanS to prevent autophosphorylation of the sensor kinases and transfer of the phosphate groups to the VanR and VanR response regulators. VanSHQ and VanSHQ abolished activation of VanR and VanR by host kinases. The phosphatase activity of VanSHQ was negatively modulated by vancomycin whereas VanSHQ prevented transcription of the resistance genes under all growth conditions. Cross-talk was detected between VanR and VanS in a null mutant. VanR is required for activation of promoters and allowing transcription of the regulatory () and resistance () genes, respectively. Under non-inducing conditions, activation of VanR by cross-talk was blocked by the presence of a multicopy plasmid carrying . Presence of the high-affinity VanR-binding sites of the regulatory region of on the multicopy vector probably sequestered VanR, thereby preventing autoactivation of the promoter. Under such circumstances, stimulation of the host kinase by glycopeptides or moenomycin was required for expression of the resistance genes.


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