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.