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

点击翻译按钮获取中文摘要

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.