The roles of fosfomycin resistant subpopulations of Escherichia coli in urinary tract infection.

大肠杆菌磷霉素耐药亚群在尿路感染中的作用。

• 批准号: 10603417
• 负责人: Tomas Alexander Bermudez
• 金额: $ 3.25万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10603417
• 关键词: Accounting; Acute; Affect; American; Amino Acids; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Bacterial Proteins; Bacteriuria; Biological Assay; Bladder; Cell Culture Techniques; Cells; Chronic; Citric Acid Cycle; Classification; Clinical; Clinical Research; Cystitis; Data; Defect; Diffusion; Disadvantaged; Drug resistance; Effectiveness; Epithelial Cells; Escherichia coli; Escherichia coli Infections; Eukaryotic Cell; European; Exposure to; Fosfomycin; Genomics; Gluconeogenesis; Glucose-6-Phosphate; Glycolysis; Glycolysis Pathway; Growth; Health care facility; Immune response; Impairment; In Vitro; Infection; Infective cystitis; Institution; Intoxication; Kinetics; Laboratories; Metabolic; Microscopy; Modeling; Multi-Drug Resistance; Mus; Mutation; Organism; Parents; Pathogenesis; Patients; Peptidoglycan; Pharmaceutical Preparations; Physiology; Predisposition; Production; Resistance; Role; Route; Sepsis; Stress; System; Techniques; Testing; Urinary tract; Urinary tract infection; Uropathogenic E. coli; Virulence; Work; drug resistant pathogen; fitness; fitness test; host colonization; insight; mouse model; mutant; novel; pathogen; response; skills; urinary

PROJECT SUMMARY/ABSTRACT Urinary tract infections (UTIs) are one of the most common bacterial infections worldwide and the bacteria that cause them are becoming increasing resistant to frontline antibiotics. As a result, last resort antibiotics, like fosfomycin, are beginning to be more frequently prescribed. Uropathogenic Escherichia coli (UPEC), which is the primary cause of UTIs, can become resistant to fosfomycin, through mutations that impair the function or production of the UhpT transporter, which imports fosfomycin into the bacterial cell. The current paradigm is that such mutations come at a fitness tradeoff because impairment of UhpT limits the import of the glycolysis intermediate glucose-6-phosphate. However, my preliminary data indicate that mutations that lead to increased resistance to fosfomycin by abrogating uhpT expression, do not impede colonization of the host urinary tract. In fact, loss of fosfomycin import demonstrates increased persistence during long-term infection. Additionally, I have shown that 77% of screened UPEC clinical isolates harbor fosfomycin resistant subpopulations. This raises the alarming hypothesis that fosfomycin resistant subpopulations arise during UTI, possibly in response to a host-imposed stress and may provide additional fitness advantages for the pathogen. I will test this hypothesis through two specific aims which will: determine the contribution of fosfomycin resistant subpopulations to UPEC pathogenesis (Aim 1) and elucidate the basis of prolonged bacteriuria during UPEC pathogenesis following loss of uhpBA (Aim 2). Together my studies will provide insights that will ultimately help us curb the onset and propagation of resistance to one of the last- resort antibiotic agents, by thoroughly elucidating novel mechanisms that lead to fosfomycin resistance during infection and gauging their fitness advantages and disadvantages in comparison to their parental strains. Through the execution of these aims, I will cultivate valuable skills in genomic analysis, advanced microscopy techniques, eukaryotic cell culture, and comprehensive analysis of host-pathogen interactions.

项目摘要/摘要 尿路感染是世界范围内最常见的细菌感染之一，而 因为他们对一线抗生素的抗药性越来越强。因此，最后的抗生素，比如 磷霉素，开始更频繁地被开出。尿路致病性大肠杆菌(UPEC)，即 尿路感染的主要原因可能是通过突变损害功能或对磷霉素产生抗药性 生产UhpT转运蛋白，将磷霉素输入细菌细胞。目前的模式是 因为UhpT的损伤限制了糖酵解的输入，所以这种突变是在适合性之间进行权衡的 中间体葡萄糖-6-磷酸。然而，我的初步数据表明，导致 通过取消uhpT的表达增加对磷霉素的抗性，不会阻碍寄主的定植 尿路。事实上，失去磷霉素进口表明，在长期感染期间，持久性增加。 此外，我已经表明77%的筛选的UPEC临床分离株对磷霉素具有耐药性。 亚群。这提出了一个令人担忧的假设，即磷霉素耐药亚群的出现 在尿路感染期间，可能是为了应对宿主施加的压力，并可能提供额外的适应能力 对病原体有利。我将通过两个具体目标来验证这一假设：确定 磷霉素耐药亚群在UPEC发病机制中的作用(目标1)并阐明 UhpBA缺失后，UPEC发病过程中菌尿延长(目标2)。一起我的学习将会 提供洞察力，最终将帮助我们遏制对最后一种 通过彻底阐明导致磷霉素耐药性的新机制，求助于抗生素 感染，并衡量他们的健康优势和劣势与其亲本品系。 通过执行这些目标，我将在基因组分析、高级显微镜方面培养有价值的技能 技术、真核细胞培养和宿主-病原体相互作用的综合分析。