Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
Antimicrob Agents Chemother. 2012 Apr;56(4):1784-96. doi: 10.1128/AAC.05869-11. Epub 2012 Jan 9.
Bacterial 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 coelicolor possesses a vanRSJKHAX gene cluster that when expressed confers resistance to both vancomycin and teicoplanin. The resistance to vancomycin is mediated by the enzymes encoded by vanKHAX, but not by vanJ. vanHAX effect a reprogramming of peptidoglycan biosynthesis, which is considered to be generic, conferring resistance to all glycopeptide antibiotics. Here, we show that vanKHAX are not in fact required for teicoplanin resistance in S. coelicolor, which instead is mediated solely by vanJ. vanJ is 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. vanJ homologues are found ubiquitously in streptomycetes and include staP from the Streptomyces toyocaensis A47934 biosynthetic gene cluster. While overexpression of staP also conferred resistance to teicoplanin, similar expression of other vanJ homologues (SCO2255, SCO7017, and SAV5946) did not. The vanJ and staP orthologues, 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.
细菌对糖肽抗生素替考拉宁的耐药性与密切相关的化合物万古霉素有一些重要的区别。这些区别目前了解甚少,但可能反映了每种抗生素作用方式的显著差异。变铅青链霉菌拥有一个 vanRSJKHAX 基因簇,当该基因簇表达时,可同时赋予对万古霉素和替考拉宁的耐药性。对万古霉素的耐药性是由 vanKHAX 编码的酶介导的,但不是由 vanJ 介导的。vanHAX 对肽聚糖生物合成进行了重新编程,这被认为是通用的,赋予了对所有糖肽抗生素的耐药性。在这里,我们表明,vanKHAX 实际上并不是变铅青链霉菌对替考拉宁耐药所必需的,而只是由 vanJ 介导的。vanJ 编码一种膜蛋白,其 C 末端活性位点朝向细胞外空间。VanJ 还赋予对替考拉宁样抗生素利福平和 A47934 的耐药性,以及对广泛的半合成替考拉宁衍生物的耐药性,但一般对具有万古霉素样结构的抗生素或半合成衍生物没有耐药性。vanJ 同源物在链霉菌中普遍存在,包括来自变铅青链霉菌 A47934 生物合成基因簇的 staP。虽然 staP 的过表达也赋予了对替考拉宁的耐药性,但其他 vanJ 同源物(SCO2255、SCO7017 和 SAV5946)的类似表达则没有。因此,vanJ 和 staP 同源物似乎代表了一个更大的蛋白质家族的一个子集,其成员在抗生素耐药性方面获得了专门的作用。对这个新家族内不同酶活性的未来特征描述将有助于确定对替考拉宁活性和耐药性很重要的分子机制。