Defining Host-pathogen Interactions in CAUTI to Guide Novel Drug Development

定义 CAUTI 中宿主-病原体相互作用以指导新药开发

• 批准号: 10371780
• 负责人: Jennifer N. Walker
• 金额: $ 13.93万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371780
• 关键词: 2-hydroxypyridine; Accounting; Affect; Age; Aging; Ammonium; Bacteremia; Bacteria; Basic Science; Binding; Binding Sites; Bioinformatics; Bladder; Blood; Carbon; Catheters; Chronic; Clinical; Collection; Complex; Data; Development; Disease; Elderly; Environment; Enzyme Kinetics; Enzymes; Epithelial; Equipment Malfunction; Escherichia coli; Exhibits; Genetic; Genetic Transcription; Genomics; Genus staphylococcus; Gram-Positive Cocci; Health Sciences; Healthcare Systems; Holoenzymes; Hospitals; In Vitro; Incontinence; Individual; Infection; Inflammation; Intervention; Lead; Longevity; Medical; Medical Device; Medical center; Methicillin Resistance; Microbial Biofilms; Microbial Genetics; Microbiology; Modeling; Molecular; Morbidity - disease rate; Mucous Membrane; Multi-Drug Resistance; Mus; Mutation; Neurogenic Bladder; Nosocomial Infections; Nucleic Acid Regulatory Sequences; Operon; Organ; Pathogenicity; Patient Care; Patients; Play; Population; Pre-Clinical Model; Predisposition; Prevention strategy; Proteins; Proteus mirabilis; Quality of life; Recombinants; Regulatory Element; Regulon; Research; Research Personnel; Role; Shock; Signal Transduction; Single Nucleotide Polymorphism; Stains; Staphylococcus aureus; Surface; Symptoms; Testing; Texas; Time; Training; Translating; Translations; Universities; Urea; Urease; Urinary tract; Urinary tract infection; Urine; Uropathogen; Virulence; Virulence Factors; age effect; age group; burden of illness; career development; catheter associated UTI; clinically relevant; crystallinity; drug development; functional genomics; high risk; improved; infection rate; infection risk; insight; interdisciplinary approach; mortality; novel therapeutics; pathogen; programs; small molecule; translational scientist; treatment strategy; urinary

PPROJECT ABSTRACT More than 30 million urinary catheters (UCs) are placed every year in the US, making them the most commonly used indwelling medical device. While short-term UC usage is common in hospitals as part of standard patient care, chronic indwelling UCs are frequently used outside the healthcare system to improve the quality of life of individuals with urinary tract abnormalities, such as incontinence and neurogenic bladder. UCs are associated with high infection rates, particularly among patients with chronic indwelling UCs. Furthermore, catheter- associated urinary tract infections (CAUTIs) can result in severe morbidity and increased mortality. CAUTI caused by bacteria with high pathogenic potential such as Staphylococcus aureus, pose additional challenges in chronically catheterized individuals. Additionally, our preliminary data suggest that S. aureus strains that cause CAUTI produce urease. This enzyme contributes to the formation of UC encrustations, which are particularly recalcitrant to treatment and lead to device failure. Thus, to gain a better understanding of the mechanisms that facilitate these common infections and inform the development of effective prevention or treatment strategies, this proposal seeks to investigate the functional and genomic role of urease in S. aureus CAUTI. My preliminary data suggest S. aureus urease is part of the carbon catabolite protein (CcpA) regulon and contributes to CAUTI during short UC dwell times. Furthermore, I have identified small molecule compounds that directly interact with the urease holoenzyme, suggesting these molecules can be optimized to develop anti-virulence therapies that inhibit urease activity and may be used to treat CAUTI caused by S. aureus or other urease-producing uropathogens. I postulate that urease is essential for chronic S. aureus CAUTI and that the enzyme is regulated as part of the CcpA regulon. Furthermore, I hypothesize that the increase in enzymatic activity observed in S. aureus strains serially collected from chronically catheterized and colonized individuals is dictated by single nucleotide polymorphisms within the regulatory elements and/or the urease operon. Using a robust collection of clinically relevant S. aureus strains recently isolated from individuals with chronic UCs, I will investigate the mechanisms that facilitate S. aureus CAUTI in three specific aims. First, I will examine the conserved genomic features and define the regulatory elements that affect S. aureus urease expression and activity. Second, I will determine the role of urease in chronic S. aureus CAUTI. Finally, I will optimize anti-virulence compounds that inhibit this enzyme. These findings may provide the insights needed to develop non-antibiotic interventions that treat recalcitrant CAUTIs and support the career development of a translational scientist focused on UTIs. The University of Texas Health Science Center and Texas Medical Center has a nationally recognized research program that offers an exceptional environment to conduct my research and receive the training needed to transition to independence.

pproject摘要 每年在美国放置超过3000万次尿导管（UCS），使其成为最常见的 使用的留置医疗设备。作为标准患者的一部分，医院中的短期UC使用很常见 护理，经常在医疗保健系统之外使用慢性带UCS来改善生活质量 尿路异常的个体，例如尿失禁和神经源性膀胱。 UCS是关联的 感染率高，尤其是在慢性居住UC的患者中。此外，导管 - 相关的尿路感染（CAUTIS）会导致严重的发病率和死亡率增加。凯蒂 由具有高致病潜力的细菌（例如金黄色葡萄球菌）引起的，构成其他挑战 在长期导管的个体中。此外，我们的初步数据表明导致的金黄色葡萄球菌菌株 癌产生尿素。这种酶有助于形成UC构造，这尤其是 顽固的治疗并导致设备故障。因此，要更好地了解 促进这些常见的感染并告知有效的预防或治疗策略的发展， 该提案旨在研究尿素酶在金黄色葡萄球菌中的功能和基因组作用。我的初步 数据表明金黄色葡萄球菌是碳分解代谢物蛋白（CCPA）调节的一部分，并有助于CAUTI 在简短的UC停留时间。此外，我已经确定了与直接相互作用的小分子化合物 脲酶全酶，表明可以优化这些分子以开发抗病毒疗法 抑制尿素酶活性，可用于治疗由金黄色葡萄球菌或其他产生的尿素 尿道病。我假设尿素对慢性金黄色葡萄球菌至关重要，并且调节酶 作为CCPA Regulon的一部分。此外，我假设在S.中观察到的酶活性的增加 从慢性导管和定殖个体中串行收集的金黄色金黄色菌株由单一决定 调节元件和/或尿素酶操纵子内的核苷酸多态性。使用强大的集合 临床上相关的金黄色葡萄球菌菌株最近从患有慢性UCS的个体中分离出来，我将研究 在三个特定目标中促进金黄色葡萄球菌的机制。首先，我将检查保守的基因组 特征并定义影响金黄色金黄色葡萄球菌表达和活性的调节元件。第二，我会的 确定尿素酶在慢性金黄色葡萄球菌中的作用。最后，我将优化抗病毒性化合物 抑制该酶。这些发现可能会提供开发非抗生素干预措施所需的见解 治疗顽固的cautis并支持专注于尿路斯的转化科学家的职业发展。这 德克萨斯大学健康科学中心和德克萨斯医学中心拥有一项全国认可的研究 提供了一个特殊环境的计划，以进行我的研究并接受所需的培训 过渡到独立。