Mutations leading to increased levels of resistance to glycopeptide antibiotics in VanB‐type enterococci

The vanB gene cluster mediates glycopeptide resistance by production of peptidoglycan precursors ending in the depsipeptide D‐alanyl‐D‐lactate (D‐Ala‐D‐Lac) instead of D‐Ala‐D‐Ala found in susceptible enterococci. Synthesis of D‐Ala‐D‐Lac and hydrolysis of D‐Ala‐D‐Ala is controlled by the VanRBSB two‐component regulatory system that activates transcription of the resistance genes in response to vancomycin but not to teicoplanin. Two substitutions (A30→G or D168→Y) in the VanSB sensor kinase resulted in induction by teicoplanin, indicating that the N‐terminal domain of the protein was involved in glycopeptide sensing. A substitution (T237→K) located in the vicinity of the putative autophosphorylation site of VanSB (H233) was associated with a constitutive phenotype and affected a conserved residue known to be critical for the phosphatase activity of related kinases. A mutant producing an impaired host D‐Ala:D‐Ala ligase required vancomycin for growth, since D‐Ala‐D‐Lac was only produced under inducing conditions. The ddl and vanSB mutations, alone or in combination, resulted in various resistance phenotypes that were determined by the amount of D‐Ala‐D‐Ala and D‐Ala‐D‐Lac incorporated into peptidoglycan precursors under different inducing conditions.

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