VanX, a bacterial d -alanyl- d -alanine dipeptidase: Resistance, immunity, or survival function?

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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 (σ 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.