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Regulated interactions between partner and non-partner sensors and response regulators that control glycopeptide resistance gene expression in enterococci

Michel Arthur

Unité des Agents Antibactériens, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15, France

Present address: Biochimie Structurale et Cellulaire, CNRS EP 1088, Université Paris-Sud, 91405 Orsay Cedex, France.

Author for correspondence: Florence Depardieu. Tel: +33 1 45 68 83 21. Fax: + 33 1 45 68 83 19. e-mail: fdepard@pasteur.fr

ABSTRACT

Transcription of the vanA and vanB glycopeptide resistance gene clusters is regulated by the VanRS and VanR_BS_B two-component regulatory systems, respectively. Histidine to glutamine substitutions were introduced at positions 164 of VanS and 233 of VanS_B to prevent autophosphorylation of the sensor kinases and transfer of the phosphate groups to the VanR and VanR_B response regulators. VanSH₁₆₄Q and VanS_BH₂₃₃Q abolished activation of VanR and VanR_B by host kinases. The phosphatase activity of VanS_BH₂₃₃Q was negatively modulated by vancomycin whereas VanSH₁₆₄Q prevented transcription of the resistance genes under all growth conditions. Cross-talk was detected between VanR_B and VanS in a vanS_B null mutant. VanR is required for activation of promoters P_R and P_H allowing transcription of the regulatory (vanRS) and resistance (vanHAXYZ) genes, respectively. Under non-inducing conditions, activation of VanR by cross-talk was blocked by the presence of a multicopy plasmid carrying P_H. Presence of the high-affinity VanR-binding sites of the regulatory region of P_H on the multicopy vector probably sequestered VanR, thereby preventing autoactivation of the P_R 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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