VanX, a bacterial D-alanyl-D-alanine dipeptidase: Resistance, immunity, orsurvival function?

The zinc containing D-alanyl-D-alanine (D-Ala-D-Ala) dipeptidase VanX has b een detected in both Grampositive and Gram-negative bacteria, where it appe ars to have adapted to at least three distinct physiological roles. In path ogenic vancomycin-resistant enterococci, vanX is part of a five-gene cluste r that is switched on to reprogram cell-wall biosynthesis to produce peptid oglycan 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 phenotypi c resistance, In the glycopeptide antibiotic producers Streptomyces toyocae nsis and Amylocatopsis orientalis, a vanHAX operon may have coevolved with antibiotic biosynthesis genes to provide immunity by reprogramming cell-wal l termini to D-Ala-D-lactate as antibiotic biosynthesis is initiated. In th e Gram-negative bacterium Escherichia call, which is never challenged by th e glycopeptide antibiotics because they cannot penetrate the outer membrane permeability barrier, the vanX homologue (ddpX) is cotranscribed with a pu tative dipeptide transport system (ddpABCDF) in stationary phase by the tra nscription factor RpoS (sigma(s)). The combined action of DdpX and the perm ease would permit hydrolysis of D-Ala-D-Ala transported back into the cytop lasm 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.