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Principal Investigator: Jennifer Nicole Walker
Organization: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
Fiscal Year: 2024
Award: $137,938
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <2(lH)-pyridinone><2-hydroxypyridine><2-pyridinone><2-pyridone><Accounting><Affect><Age><Aging><Ammonium><Bacteremia><Bacteria><Basic Research><Basic Science><Binding><Binding Sites><Bio-Informatics><Bioinformatics><Bladder><Bladder Urinary System><Blood><Blood Reticuloendothelial System><CO2><Carbamide><Carbon><Carbon Dioxide><Carbonic Anhydride><Catheterization><Catheters><Cell Communication and Signaling><Cell Signaling><Chronic><Circulatory Collapse><Clinical><Collection><Combining Site><Complex><Data><Development><Device Failures><Disease><Disorder><E coli><E. coli><Elaqua XX><Elderly><Environment><Enzyme Gene><Enzyme Inhibition><Enzyme Kinetics><Enzymes><Epithelium><Equipment Malfunction><Escherichia coli><Exhibits><Gene Transcription><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genomics><Genus staphylococcus><Gram-Positive Cocci><Health Care Systems><Health Sciences><Healthcare Systems><Holoenzymes><Hospital Infections><Hospital acquired infection><Hospitals><Hydrolysis><In Vitro><Incontinence><Individual><Infection><Inflammation><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigators><Medical Device><Medical center><Methicillin Resistance><Mice><Mice Mammals><Microbial Biofilms><Microbial Genetics><Microbiology><Modeling><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Tissue><Mucous Membrane><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Murine><Mus><Mutation><Neurogenic Bladder><Neurogenic Bladder Disorder><Neurogenic Urinary Bladder Disorder><Neuropathic Bladder><Nosocomial Infections><Nucleic Acid Regulator Regions><Nucleic Acid Regulatory Sequences><Operon><Organ><P mirabilis><P. mirabilis><Pathogenicity><Pathogenicity Factors><Patient Care><Patient Care Delivery><Patients><Population><Pre-Clinical Model><Preclinical Models><Predisposition><Preventative strategy><Prevention strategy><Preventive strategy><Proteins><Proteus mirabilis><QOL><Quality of life><RNA Expression><Reactive Site><Recombinants><Regulatory Element><Regulatory Regions><Regulon><Reporting><Research><Research Personnel><Researchers><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistance to methicillin><Resistant to Multiple Drug><Resistant to methicillin><Resistant to multi-drug><Resistant to multidrug><Role><S aureus><S. aureus><Shock><Signal Transduction><Signal Transduction Systems><Signaling><Single Base Polymorphism><Single Nucleotide Polymorphism><Staining method><Stains><Staph aureus><Staphylococcus><Staphylococcus aureus><Surface><Susceptibility><Symptoms><Testing><Texas><Training><Transcription><Translating><Translations><Universities><Urea><Urea Amidohydrolase><Urea Carbamide><Ureaphil><Urease><Urinary Bladder Neurogenic Dysfunction><Urinary tract><Urinary tract infection><Urinary tract infectious disease><Urine><Uropathogen><Virulence><Virulence Factors><advanced age><age associated effects><age effect><age group><age related effects><ages><aging effect><bacteraemia><bacterial sepsis><biofilm><biological signal transduction><biomedical implant><burden of disease><burden of illness><care for patients><care of patients><career development><caring for patients><catheter associated UTI><catheter associated urinary tract infection><circulatory shock><clinical relevance><clinically relevant><developmental><disease burden><drug development><genetic regulatory element><genome mutation><geriatric><high risk><impact of age><implant device><implantable device><improved><indwelling device><infection rate><infection risk><influence of age><insight><institutional infection><interdisciplinary approach><interventional strategy><irritation><isolated individuals><isolated people><life span><lifespan><lonely individuals><lonely people><methicillin resistant><mortality><multi-drug resistant><multidisciplinary approach><multidrug resistant><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><pathogen><programs><rate of infection><senior citizen><shocks><single nucleotide variant><small molecule><social role><translation><translational investigator><translational researcher><translational scientist><treatment strategy><urinary><urinary bladder><urinary infection><urinary tract catheter infection>