A Novel Membrane Protein, VanJ, Conferring Resistance to Teicoplanin
ABSTRACTBacterial resistance to the glycopeptide antibiotic teicoplanin shows some important differences from the closely related compound vancomycin. They are currently poorly understood but may reflect significant differences in the mode of action of each antibiotic.Streptomyces coelicolorpossesses avanRSJKHAXgene cluster that when expressed confers resistance to both vancomycin and teicoplanin. The resistance to vancomycin is mediated by the enzymes encoded byvanKHAX, but not byvanJ. vanHAXeffect a reprogramming of peptidoglycan biosynthesis, which is considered to be generic, conferring resistance to all glycopeptide antibiotics. Here, we show thatvanKHAXare not in fact required for teicoplanin resistance inS. coelicolor, which instead is mediated solely byvanJ. vanJis shown to encode a membrane protein oriented with its C-terminal active site exposed to the extracytoplasmic space. VanJ also confers resistance to the teicoplanin-like antibiotics ristocetin and A47934 and to a broad range of semisynthetic teicoplanin derivatives, but not generally to antibiotics or semisynthetic derivatives with vancomycin-like structures.vanJhomologues are found ubiquitously in streptomycetes and includestaPfrom theStreptomyces toyocaensisA47934 biosynthetic gene cluster. While overexpression ofstaPalso conferred resistance to teicoplanin, similar expression of othervanJhomologues (SCO2255, SCO7017, and SAV5946) did not. ThevanJandstaPorthologues, therefore, appear to represent a subset of a larger protein family whose members have acquired specialist roles in antibiotic resistance. Future characterization of the divergent enzymatic activity within this new family will contribute to defining the molecular mechanisms important for teicoplanin activity and resistance.