Molecular Clonality of Uropathogenic E. Coli

尿路致病性大肠杆菌的分子克隆

• 批准号: 10393561
• 负责人: EVGENI Veniaminovic SOKURENKO
• 金额: $ 75.09万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-11-19 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10393561
• 关键词: Antibiotic Resistance; Antibiotics; Area; Bacteremia; Bacterial Infections; Bacteriophages; Bacteriuria; Bladder; Clinical; Clonality; Collection; Communities; Data; Data Analyses; Ecology; Epidemiology; Escherichia coli; Family; Fluoroquinolones; Frequencies; Funding; Gene Transfer; General Population; Genetic Transcription; Genetic Variation; Genomics; Goals; Health Personnel; Horizontal Gene Transfer; Human; Infection; Integration Host Factors; Medicine; Molecular; Multi-Drug Resistance; Mutation; Pathogenicity; Patients; Pattern; Population; Prophylactic treatment; Public Health; Publishing; Recommendation; Research; Risk; Sample Size; Sampling; Single Nucleotide Polymorphism; Symptoms; Testing; Therapeutic; Time; Urinary tract; Urinary tract infection; Urine; Uropathogenic E. coli; Vaccines; Virulence; Washington; Woman; Work; antagonist; bacterial resistance; base; clinical risk; cohort; emerging antimicrobial resistance; enteric infection; expectation; fluoroquinolone resistance; genome-wide; gut colonization; human pathogen; insertion/deletion mutation; member; nosocomial UTI; novel; pandemic disease; resistant strain; sound; urovirulent isolates

Our long-term goal is to advance the understanding, at the molecular level, of the pathogenicity and epidemiology of uropathogenic Escherichia coli strains to better target treatment and prophylaxis of urinary tract infections (UTIs), reduce antibiotic resistance, and provide information on possible targets for vaccines and antibiotics. The most common cause of fluoroquinolone and multi-drug resistant UTIs are two E. coli strains that comprise clonal groups ST131-H30 and ST1193. Those pandemic multi-drug resistant strains (PMDR) have emerged 1-2 decades ago, are globally spread and, combined, are responsible for 60- 80% of the antibiotic-resistant UTIs. At the same time, PMDR appears to be able persisting for many months, possibly years in the gut and urinary bladder of healthy women, without them having symptoms of UTI or taking antibiotics. The objective of the proposed work is to investigate in detail the frequency, patterns and clinical risks of asymptomatic gut and bladder carriage of PMDR, identify possible means of the carriers de-colonization and compare on a genome-wide scale the PMDR isolates from women without and with UTI. Our preliminary data support that we can investigate sizeable samples of fecal and urine samples, establish the clonal identity of fresh isolates, and determine genome-wide the pathogenicity-adaptive genetic changes. We will determine how mutational changes (single nucleotide polymorphisms, small insertions/deletions, etc.) and horizontal gene transfer contribute to the urovirulence of PMDR. For this, we will employ a population genomics- based analysis to trace the mutations and gene transfer, followed by assessment of the functional significance of the representative positively selected loci in PMDR. practical terms, accomplishment of the proposed studies will advance at the molecular level our understanding of the ecology, pathogenicity, and epidemiology of antibiotic-resistant uropathogenic E. coli and will provide information on possible targets for vaccines, antibiotics, or other therapeutics.

我们的长期目标是在分子水平上加深对尿路致病性大肠杆菌菌株的致病性和流行病学的了解，以更好地针对尿路感染（UTI）的治疗和预防，减少抗生素耐药性，并提供有关可能的信息。疫苗和抗生素的靶点。氟喹诺酮类和多药耐药尿路感染最常见的原因是两个大肠杆菌。包含克隆群ST 131-H30和ST 1193的大肠杆菌菌株。这些流行性多药耐药菌株（PMDR）在1- 20年前出现，在全球范围内传播，合并起来造成了60- 80%的耐药性UTI。与此同时，PMDR似乎能够在健康女性的肠道和膀胱中持续数月，甚至数年，而不会出现UTI症状或服用抗生素。拟议工作的目的是详细调查无症状肠道和膀胱携带PMDR的频率、模式和临床风险，确定携带者去定植的可能方法，并在全基因组范围内比较来自无UTI和有UTI女性的PMDR分离株。我们的初步数据支持，我们可以调查粪便和尿液样本的大样本，建立新鲜分离株的克隆身份，并确定全基因组的致病性适应性遗传变化。我们将确定突变变化（单核苷酸多态性，小插入/缺失等）水平基因转移与PMDR的尿毒力有关。为此，我们将采用基于群体基因组学的分析来追踪突变和基因转移，然后评估PMDR中代表性阳性选择基因座的功能意义。从实际意义上说，这些研究的完成将在分子水平上推进我们对耐药尿路致病性大肠杆菌的生态学、致病性和流行病学的理解。大肠杆菌，并将提供有关疫苗，抗生素或其他疗法的可能目标的信息。