title: VanX, a bacterial D-alanyl-D-alanine dipeptidase: resistance, immunity, or survival function?
abstract: The zinc-containing D-alanyl-D-alanine (D-Ala-D-Ala) dipeptidase VanX has been detected in both Gram-positive and Gram-negative bacteria, where it appears to have adapted to at least three distinct physiological roles. In pathogenic vancomycin-resistant enterococci, vanX is part of a five-gene cluster that is switched on to reprogram cell-wall biosynthesis to produce peptidoglycan chain precursors terminating in D-alanyl-D-lactate (D-Ala-D-lactate) rather than D-Ala-D-Ala. The modified peptidoglycan exhibits a 1, 000-fold decrease in affinity for vancomycin, accounting for the observed phenotypic resistance. In the glycopeptide antibiotic producers Streptomyces toyocaensis and Amylocatopsis orientalis, a vanHAX operon may have coevolved with antibiotic biosynthesis genes to provide immunity by reprogramming cell-wall termini to D-Ala-D-lactate as antibiotic biosynthesis is initiated. In the Gram-negative bacterium Escherichia coli, which is never challenged by the glycopeptide antibiotics because they cannot penetrate the outer membrane permeability barrier, the vanX homologue (ddpX) is cotranscribed with a putative dipeptide transport system (ddpABCDF) in stationary phase by the transcription factor RpoS (sigma(s)). The combined action of DdpX and the permease would permit hydrolysis of D-Ala-D-Ala transported back into the cytoplasm from the periplasm as cell-wall crosslinks are refashioned. The D-Ala product could then be oxidized as an energy source for cell survival under starvation conditions.
authors.affiliation: Biological Chemistry and Molecular Pharmacology Department, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: I A
authors.initials: IA
authors.lastname: Lessard
authors.forename: C T
authors.initials: CT
authors.lastname: Walsh
mesh_terms: D001419:Bacteria / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D001426:Bacterial Proteins / Q000502:physiology*; D002470:Cell Survival; D004150:Dipeptidases / Q000502:physiology*; D004352:Drug Resistance, Microbial; D004926:Escherichia coli / Q000201:enzymology; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase; D014640:Vancomycin / Q000096:biosynthesis* / Q000494:pharmacology
chemical_list: D001426:Bacterial Proteins; D014640:Vancomycin; D004150:Dipeptidases; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase; C091956:VanX dipeptidase