Aminoglycoside Resistance in Enterococci

肠球菌是美国医院感染中最常见的细菌之一。 严重肠球菌感染的最佳抗菌治疗需要使用协同组合 一种细胞壁活性物质，如氨苄西林或万古霉素，含有氨基糖苷，这会导致 对肠球菌的杀菌活性。然而，许多肠球菌菌株已经获得了氨基糖苷类。 编码氨基糖苷类修饰酶的抗性基因会消除这种协同作用 杀菌作用。因此，在许多医学中心，对氨基糖苷类药物的耐药性已成为主要的 治疗挑战，排除了对大多数肠球菌感染的最佳治疗。高水平 肠球菌对临床重要氨基糖苷类庆大霉素的耐药性是由APH(2“)介导的 酵素。我们建议通过(1)进行以下操作来详细研究这些氨基糖苷磷酸转移酶 这些氨基糖苷类修饰酶的动力学研究和化学机理探讨(2) 研究保守氨基酸残基在催化机理中的作用；(3)研究 这些肠球菌酶中的一种向更高水平和更广泛的谱进化 氨基糖苷类耐药。更清楚地了解这些酶和它们之间的相互作用 底物(氨基糖苷类和三磷酸腺苷辅助因子)，以及酶的进化以产生 更多样化的阵列将促进新型氨基糖苷类药物的开发，无论是作为 这些酶或作为酶抑制剂，以克服这些酶所产生的抗性。网络技术的演变 肠球菌氨基糖苷类磷酸转移酶中的一种朝着更高水平和更广泛的方向发展 氨基糖苷类抗生素耐药性的研究将使预测哪些氨基糖苷类抗生素更有可能对 随着耐药性向其他氨基糖苷类药物的发展，在未来保持它们的活性。在这两方面都取得了进展 这些方向将是治疗严重肠球菌感染的重要进展。 有效治疗由耐药肠球菌引起的严重感染已成为一项主要任务 临床挑战。我们建议研究肠球菌对一类抗生素的耐药机制。 名为氨基糖苷类。我们的研究结果将有助于开发新的抗生素和 治疗肠球菌感染的方法，这种感染正在迅速出现，对公众健康构成严重威胁。

Enterococci are among the most common bacteria isolated in nosocomial infections in the United States. Optimal antimicrobial therapy for serious enterococcal infections requires the use of synergistic combinations of a cell wall-active agent, such as ampicillin or vancomycin,with an aminoglycoside, which results in bactericidal activity against enterococci. However, many enterococcal strains have acquired aminoglycoside resistance genes that encode aminoglycoside-modifying enzymes, which eliminate this synergistic bactericidal effect. Thus, in many medical centers resistance to aminoglycosides has emerged as a major therapeutic challenge, precluding optimal therapy for the majority of enterococcal infections. High-level resistance to the clinically important aminoglycoside gentamicin in enterococci is mediated by APH(2") enzymes. We propose to study these aminoglycoside phosphotransferases in detail by (1) performing kinetics studies and investigating chemical mechanisms of these aminoglycoside-modifying enzymes; (2) investigating the roles that conserved amino acid residues play in the catalytic mechanism; and (3) studying evolution of one of these enterococcal enzymes toward higher levels and broader spectrums of aminoglycoside resistance. A clearer understanding of the interaction between these enzymes and their substrates (both aminoglycosides and the ATP cofactor), and of the evolution of the enzymes to produce a more diverse array would facilitate the development of novel aminoglycosides, either as poor substrates of the enzymes or as enzyme inhibitors, to overcome resistance conferred by these enzymes. The evolution of one of these enterococcal aminoglycoside phosphotransferases toward higher levels and broader spectrums of aminoglycoside resistance will enable predictions of which aminoglycoside antibiotics are more likely to retain their activity in the future as resistance evolves toward other aminoglycosides. Progress in either of these directions would be an important advance in the treatment of serious enterococcal infections. Effective treatment of serious infections caused by antibiotic-resistant enterococci has become a major clinical challenge. We propose to study mechanisms of resistance in enterococci to a class of antibiotics called the aminoglycosides. Results from our study will help in the development of new antibiotics and approaches to treat enterococcal infections, which are emerging rapidly as a serious threat to public health.