MECHANISMS OF GLYCOPEPTIDE RESISTANCE IN STAPHYLOCOCCI

描述(摘自申请者摘要)：葡萄球菌 物种是医院感染的主要原因，各种 影响ALL患者的感染和毒素介导的综合征 年龄。糖肽(GP)、万古霉素(Vm)和替考拉宁(TCO)分别为 治疗甲氧西林耐药的最可靠替代品 对β-内酰胺类和广谱耐药的葡萄球菌 抗生素。因此，临床上葡萄球菌的出现 敏感度、异质电阻和True降低的分离株 对GPS的抵制令人担忧。调查人员的研究是 目的明确葡萄球菌对Vm和TCO的耐药机制。 耐药性可能是复杂的和多因素的，因此需要 一种多方面的调查方法。在这方面，他们建议 一个耐VM实验室的转座子(TN)突变体的特征 金黄色葡萄球菌的分离和TN诱变 其他临床分离的对VM和TCO耐药的金黄色葡萄球菌 凝固酶阴性的耐VM溶血葡萄球菌分离株。他们还计划 筛选从选定的糖肽制备的质粒库- 耐药临床和实验室分离株(S)，用于能够 在对VM敏感的分离株中授予VM抗性以确定 质粒插入在介导抗药性中的作用。他们还提议 用全局随机方法确定糖肽抗性决定因素 抗性和感病品系基因组DNA和mRNA的比较 限制性标志物基因组扫描和mRNA差异分析 旨在比较耐gp金黄色葡萄球菌和敏感金黄色葡萄球菌 分离株。进行这些活动的决定将部分基于什么 经TN诱变和质粒文库筛选得知。 他们还将确定是否有PBP2的角色，可在 许多临床和实验室衍生的Vm耐药性增加 通过使PBPB基因失活并评估其对 金黄色葡萄球菌的耐药性和异质性耐药 金黄色葡萄球菌菌血症模型开始澄清一些重要问题 关于金黄色葡萄球菌对gp的耐药性。这些研究应该导致一种 了解葡萄球菌抵抗GPS和 可以提供抗菌剂针对的新的蛋白质靶点 可用于治疗由GP引起的葡萄球菌感染 耐药菌株。

DESCRIPTION (Adapted from the Applicant's Abstract): Staphylococcal species are a leading cause of nosocomial infections and a variety of infections and toxin mediated syndromes that affect patients of all ages. The glycopeptides (GP) vancomycin (Vm) and teicoplanin (Tco) are the most reliable alternatives for treatment of methicillin-resistant staphylococci, which are resistant to beta-lactams and a wide spectrum of antibiotics. Therefore, the emergence of clinical staphylococcal isolates with decreased susceptibility, heteroresistance, and true resistance to Gps has been alarming. The investigators' studies are aimed at identifying Vm and Tco resistance mechanisms in staphylococci. Resistance is likely to be complex and multifactorial and, thus, require a multifaceted investigative approach. In this regard, they propose to characterize a transposon (Tn) mutant of a Vm-resistant laboratory derived Staphylococcus aureus isolate and to perform Tn mutagenesis on other clinical Vm- and Tco-resistant S. aureus isolates and on a coagulase negative Vm-resistant S. haemolyticus isolate. They also plan to screen plasmid libraries prepared from selected glycopeptide- resistant clinical and laboratory isolate(s) for inserts capable of conferring Vm-resistance in Vm-susceptible isolates to determine the role of the plasmid insert in mediating resistance. They also propose to identify glycopeptide resistance determinants by global, random comparisons of genomic DNA and mRNA from resistant and susceptible isolates by restriction landmark genomic scanning and mRNA differential display aimed at comparing GP-resistant and -susceptible S. aureus isolates. The decision to undertake these will be based in part on what was learned with Tn mutagenesis and screening of the plasmid libraries. They will also determine whether there is a role for PBP2, found in increased abundance in many clinical and laboratory derived Vm-resistant isolates, by inactivating the pbpB gene and evaluating its effect on resistance and heteroresistance in staphylococci and employ an avian model of S. aureus bacteremia to begin to clarify some important issues regarding GP-resistance in S. aureus. These studies should lead to an understanding of the mechanisms by which staphylococci resist Gps and may provide novel protein targets against which antimicrobial agents could be designed to treat staphylococcal infections caused by GP resistant isolates.