Molecular Clonality of Uropathogenic E. Coli

我们的长期目标是在分子水平上促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，以更好地针对尿路感染(UTIs)的治疗和预防，减少抗生素耐药性，并提供有关疫苗和抗生素可能靶标的信息。氟喹诺酮类药物和多药耐药尿路感染最常见的原因是两株由克隆群ST131-H30和ST1193组成的大肠杆菌。这些大流行多药耐药株(PMDR)在1-20年前出现，在全球范围内传播，加在一起，造成了60-80%的耐抗生素尿路感染。与此同时，经前多药耐药似乎能够在健康妇女的肠道和膀胱中持续数月，甚至数年，而不会出现尿路感染症状或服用抗生素。这项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，确定可能的携带者去殖民的方法，并在全基因组范围内比较没有和有UTI的妇女的PMDR分离株。我们的初步数据支持我们可以调查大量的粪便和尿液样本，建立新鲜分离物的克隆鉴定，并确定全基因组范围内的致病性适应性基因变化。我们将确定突变是如何变化的(单核苷酸多态、小插入/小缺失等)。水平基因转移有助于PMDR的尿毒力。为此，我们将使用基于群体基因组学的分析来追踪突变和基因转移，然后评估具有代表性的阳性选择的基因座在PMDR中的功能意义。实际上，拟议研究的完成将在分子水平上促进我们对耐药尿路致病大肠杆菌的生态学、致病性和流行病学的理解，并将为疫苗、抗生素或其他治疗药物的可能靶标提供信息。

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.