Molecular Clonality of Uropathogenic E. Coli

尿路致病性大肠杆菌的分子克隆

基本信息

批准号：
10155395
负责人：
EVGENI Veniaminovic SOKURENKO
金额：
$ 74.77万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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/10155395
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 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

项目摘要

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增进对尿路致病性大肠杆菌菌株的致病性和流行病学的了解，以便更好地针对尿路感染 (UTI) 进行治疗和预防，减少抗生素耐药性，并提供有关可能目标的信息用于疫苗和抗生素。氟喹诺酮类药物和多重耐药性尿路感染的最常见原因是两种大肠杆菌菌株，其中包括克隆群 ST131-H30 和 ST1193。这些大流行性多重耐药菌株 (PMDR) 已在 1-2 十年前出现，在全球范围内传播，合计占抗生素耐药性尿路感染的 60-80%。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，而她们不会出现尿路感染症状或服用抗生素。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从无症状的女性中分离出的 PMDR。以及尿路感染。我们的初步数据支持我们可以研究大量的粪便和尿液样本，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）和水平基因转移如何影响 PMDR 的尿毒力。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 中代表性阳性选择位点的功能意义。实际上，拟议研究的完成将在分子水平上增进我们对抗生素耐药性尿路致病性大肠杆菌的生态学、致病性和流行病学的理解，并将提供有关疫苗、抗生素或其他治疗方法的可能靶点的信息。