COMBATTING QUINOLONE ANTIMICROBIAL RESISTANCE

对抗喹诺酮类抗菌药物耐药性

• 批准号: 6729491
• 负责人: LYNN ZECHIEDRICH
• 金额: $ 33.86万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729491
• 关键词: DNA topoisomerases; Escherichia coli; antiinfective agents; bacterial genetics; bioinformatics; clinical research; drug resistance; functional /structural genomics; gene environment interaction; gene interaction; gene mutation; genome; high throughput technology; human population study; human subject; membrane transport proteins; molecular cloning; multidrug resistance; patient oriented research; quinoline; statistics /biometry

DESCRIPTION (provided by applicant): Quinolones are some of the most frequently used, broad-spectrum antimicrobial agents. Resistance to these drugs has become a critical public health problem. Mutations in the drug target topoisomerases that result in drug resistance are well documented. In addition, overproduction of the multidrug efflux pump AcrAB has been reported to result in quinolone resistance in clinical isolates of E. coli. Our long-range goal is to determine how bacteria respond to exposure to quinolone agents and to use this knowledge to design more effective treatments. A goal of the present proposal is to identify the genetic alterations that lead to quinolone resistance in clinical E. coli strains and to determine the interrelationship between levels and frequency of quinolone resistance, the mutations, and other patient covariates. The central hypothesis is that following quinolone treatment, mutations conferring resistance occur additively, beginning with mutations in the topoisomerases and ultimately including overproduction of AcrAB and that the most resistant isolates contain additional mutations, including another multidrug efflux pump. Preliminary data support these hypotheses. Overproduction of any multidrug efflux pump has far reaching therapeutic consequences; antimicrobial agents from multiple different categories, in addition to the quinolones, would be ineffective against these bacteria. With the combined basic, clinical, statistical, genomic, and bioinformatic expertise of the investigators and the size of our patient population, we are uniquely poised to carry out the following specific aims: (1) Identify and categorize genetic alterations that cause quinolone resistance in clinical isolates. We will use high through-put methods to detect mutations in the genes that encode quinolone resistance. Statistical methods will be used to analyze potential interrelationships between the mutations. (2) Perform a prospective analysis of patient data. We will: (a) use the high-throughput methods developed in specific aim 1 to determine the genetic alterations occurring in E. coli isolated from patients hospitalized in the Texas Medical Center compared to isolates from various consortia around the world; (b) perform genome typing; (c) analyze these data with respect to demographic and clinical data for the patients to determine the probable causes of quinolone resistance. Until we have a better understanding of the mechanisms used by bacteria to cope with drug pressure, we cannot design better inhibitors or control antimicrobial resistant infections.

描述（由申请人提供）：喹诺酮是一些最常用的，广谱的抗菌剂。对这些药物的抵抗已成为关键的公共卫生问题。药物靶标拓扑异构酶的突变已充分记录。此外，据报道，多药于外排泵的过量生产会导致大肠杆菌临床分离株的奎诺酮抗性。 我们的远程目标是确定细菌如何应对暴露于奎诺酮剂的暴露，并利用这些知识来设计更有效的治疗方法。本提案的一个目的是确定导致临床大肠杆菌菌株中奎诺酮抗性的遗传改变，并确定奎诺酮抗性，突变和其他患者协变量之间的水平和频率之间的相互关系。中心假设是，在喹诺酮治疗后，突变赋予抗性性，从拓扑异构酶中的突变开始，最终包括过度生产acrab，最具耐药性的分离株含有其他突变，包括另一种多剂量外排泵。初步数据支持这些假设。过量生产任何多重外排泵具有远远达到治疗后果。来自多个不同类别的抗菌剂，除了喹诺酮类药物外，还将对这些细菌有效。 凭借研究人员的基本，临床，统计，基因组和生物信息学专业知识以及患者人群的规模，我们有独特的准备来实现以下特定目标： （1）识别并分类遗传改变，从而在临床分离株中引起奎诺酮抗性。我们将使用较高的贯穿方法来检测编码奎诺酮抗性的基因中的突变。统计方法将用于分析突变之间的潜在相互关系。 （2）对患者数据进行前瞻性分析。我们将：（a）使用特定目的1中开发的高通量方法来确定与来自德克萨斯州医疗中心住院的患者分离的大肠杆菌中发生的遗传改变，与来自世界各地各种财团的分离株相比； （b）执行基因组键入； （c）分析这些数据有关患者的人口统计学和临床​​数据，以确定奎诺酮抗性的可能原因。除非我们对细菌用于应对药物压力的机制有更好的了解，否则我们无法设计更好的抑制剂或对照抗菌抗性感染。