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

项目摘要 在美国，每年放置的导尿管(UC)超过3000万，使其成为最常见的 用过的留置医疗器械。虽然短期UC使用在医院作为标准患者的一部分很常见 护理，慢性留置UC经常在医疗系统之外使用，以提高患者的生活质量 有尿路异常的个人，如大小便失禁和神经性膀胱。关联的UCS 感染率高，特别是在慢性留置UC患者中。此外，导尿管- 相关的尿路感染(CAUTIs)可导致严重的发病率和死亡率增加。CAUTI 由金黄色葡萄球菌等高致病潜力细菌引起的，带来了额外的挑战 在长期留置尿管的个体中。此外，我们的初步数据表明，导致金黄色葡萄球菌 CAUTI产尿素酶。这种酶有助于UC结痂的形成，尤其是结痂 顽固不化的治疗，导致设备故障。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战略提供信息； 本研究旨在研究金黄色葡萄球菌尿素酶的功能和基因组功能。我的初选 数据表明，金黄色葡萄球菌尿素酶是碳分解代谢蛋白(CCPA)调节子的一部分，与CAUTI有关 在短暂的UC驻留时间内。此外，我已经确定了直接与之相互作用的小分子化合物 尿素酶全酶，这表明这些分子可以被优化来开发抗毒力疗法 抑制尿素酶活性，可用于治疗金黄色葡萄球菌或其他产尿素酶引起的CAUTI 泌尿系病原体。我推测，尿素酶对慢性金黄色葡萄球菌是必不可少的，而且该酶是受调节的。 作为CCPA规则的一部分。此外，我假设S。 从长期留置尿管和定居的人身上连续收集的金黄色葡萄球菌菌株由单一 调节元件和/或尿素酶操纵子内的核苷酸多态。使用健壮的集合 最近从慢性UC患者身上分离出的临床相关金黄色葡萄球菌菌株，我将调查 促进金黄色葡萄球菌CAUTI达到三个特定目的的机制。首先，我将检查保守的基因组 并定义了影响金黄色葡萄球菌尿素酶表达和活性的调控元件。第二，我会 确定尿素酶在慢性金黄色葡萄球菌感染中的作用。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必要的见解 治疗顽固性尿路感染，并支持专注于尿路感染的翻译科学家的职业发展。这个 德克萨斯大学健康科学中心和德克萨斯医学中心有一项全国公认的研究 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 向独立过渡。

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.