Molecular Clonality of Uropathogenic E. Coli

我们的长期目标是在分子水平上提高对尿路致病性大肠杆菌菌株的致病性和流行病学的理解，以更好地靶向治疗和预防尿路感染（uti），减少抗生素耐药性，并提供有关疫苗和抗生素可能靶点的信息。氟喹诺酮类和多重耐药尿路感染的最常见原因是两种大肠杆菌菌株，包括ST131-H30和ST1193克隆群。这些大流行多重耐药菌株（PMDR）是在1-2年前出现的，在全球传播，加起来造成了60% - 80%的耐抗生素尿路感染。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，而不会出现尿路感染的症状或服用抗生素。本研究的目的是详细研究PMDR无症状肠道和膀胱携带的频率、模式和临床风险，确定携带者去定植的可能手段，并在全基因组范围内比较无尿路感染和有尿路感染的女性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，建立新鲜分离株的克隆特性，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的泌尿毒性。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。实际而言，拟议研究的完成将在分子水平上推进我们对耐抗生素尿路致病性大肠杆菌的生态学、致病性和流行病学的理解，并将为疫苗、抗生素或其他治疗方法的可能靶点提供信息。

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.