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: 10543503
• 负责人: Jennifer N. Walker
• 金额: $ 13.78万
• 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/10543503
• 关键词: 2-hydroxypyridine; Accounting; Affect; Age; Aging; Ammonium; Bacteremia; Bacteria; Basic Science; Binding; Binding Sites; Bioinformatics; Bladder; Blood; Carbon; Carbon Dioxide; Catheterization; Catheters; Chronic; Clinical; Collection; Complex; Data; Development; Disease; Elderly; Environment; Enzyme Inhibition; Enzyme Kinetics; Enzymes; Epithelium; Equipment Malfunction; Escherichia coli; Exhibits; Genetic; Genetic Transcription; Genomics; Genus staphylococcus; Gram-Positive Cocci; Health Sciences; Healthcare Systems; Holoenzymes; Hospitals; Hydrolysis; In Vitro; Incontinence; Individual; Infection; Inflammation; Intervention; Longevity; 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; Population; Pre-Clinical Model; Predisposition; Prevention strategy; Proteins; Proteus mirabilis; Quality of life; Recombinants; Regulatory Element; Regulon; Reporting; Research; Research Personnel; Role; Shock; Signal Transduction; Single Nucleotide Polymorphism; Stains; Staphylococcus aureus; Surface; Symptoms; Testing; Texas; 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; drug development; high risk; implantable device; improved; infection rate; infection risk; insight; interdisciplinary approach; irritation; lonely individuals; mortality; novel therapeutic intervention; 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.

项目摘要 在美国，每年放置超过3000万根导尿管（UC），使其成为最常见的导尿管。 使用留置医疗器械。虽然短期UC使用在医院中作为标准患者的一部分很常见， 长期留置UC经常在医疗保健系统之外使用，以改善患者的生活质量。 患有泌尿道异常的个体，如尿失禁和神经源性膀胱。UC与 感染率很高，特别是在慢性留置UC患者中。此外，导管- 相关的尿路感染（尿路感染）可导致严重的发病率和增加的死亡率。CAUTI 由具有高致病潜力的细菌（如金黄色葡萄球菌）引起的感染， 在长期插管的人。此外，我们的初步数据表明，S。金黄色葡萄球菌 产尿素酶。这种酶有助于UC结壳的形成， 妨碍治疗并导致器械失效。因此，为了更好地了解 促进这些常见感染，并为制定有效的预防或治疗策略提供信息， 该建议试图研究尿素酶在S.金黄色葡萄球菌我的初步 数据表明S.金黄色葡萄球菌尿素酶是碳分解代谢物蛋白（CcpA）调节子的一部分，并有助于CCPTI 在短的UC停留时间内。此外，我还发现了一些小分子化合物， 尿素酶全酶，这表明这些分子可以优化开发抗病毒疗法， 抑制尿素酶活性，可用于治疗链球菌引起的呼吸道感染。金黄色葡萄球菌或其他产尿素酶的 泌尿病原体我假定尿素酶是慢性S。金黄色葡萄球菌的酶抑制剂和酶的调节 作为CcpA调节子的一部分此外，我推测在S. 从长期插管和定殖的个体连续收集的金黄色葡萄球菌菌株由单个 调控元件和/或尿素酶操纵子内的核苷酸多态性。使用强大的 临床相关的S.最近从慢性UC患者中分离出的金黄色葡萄球菌菌株， 促进S.金葡菌的三个具体目标。首先，我将研究保守的基因组 特征和定义影响S的调节元件。金黄色葡萄球菌尿素酶的表达和活性。第二，我会 确定尿素酶在慢性S.金黄色葡萄球菌最后，我将优化抗毒性化合物， 抑制这种酶。这些发现可能为开发非抗生素干预措施提供所需的见解， 治疗顽固性尿路感染，并支持专注于尿路感染的转化科学家的职业发展。的 得克萨斯大学健康科学中心和得克萨斯医学中心有一个全国公认的研究 该计划提供了一个特殊的环境来进行我的研究，并接受所需的培训， 过渡到独立。