Urinary Tract Infection Model Research Articles

Investigating inhibitors of 1-deoxy-d-xylulose 5-phosphate synthase in a mouse model of UTI.

The rising rate of antimicrobial resistance continues to threaten global public health. Further hastening antimicrobial resistance is the lack of new antibiotics against new targets. The bacterial enzyme, 1-deoxy-d-xylulose 5-phosphate synthase (DXPS), is thought to play important roles in central metabolism, including processes required for pathogen adaptation to fluctuating host environments. Thus, impairing DXPS function represents a possible new antibacterial strategy. We previously investigated a DXPS-dependent metabolic adaptation as a potential target in uropathogenic Escherichia coli (UPEC) associated with urinary tract infection (UTI), using the DXPS-selective inhibitor butyl acetylphosphonate (BAP). However, investigations of DXPS inhibitors in vivo have not been conducted. The goal of the present study is to advance DXPS inhibitors as in vivo probes and assess the potential of inhibiting DXPS as a strategy to prevent UTI in vivo. We show that BAP was well-tolerated at high doses in mice and displayed a favorable pharmacokinetic profile for studies in a mouse model of UTI. Further, an alkyl acetylphosphonate prodrug (homopropargyl acetylphosphonate, pro-hpAP) was significantly more potent against UPEC in urine culture and exhibited good exposure in the urinary tract after systemic dosing. Prophylactic treatment with either BAP or pro-hpAP led to a partial protective effect against UTI, with the prodrug displaying improved efficacy compared to BAP. Overall, our results highlight the potential for DXPS inhibitors as in vivo probes and establish preliminary evidence that inhibiting DXPS impairs UPEC colonization in a mouse model of UTI.IMPORTANCENew antibiotics against new targets are needed to prevent an antimicrobial resistance crisis. Unfortunately, antibiotic discovery has slowed, and many newly FDA-approved antibiotics do not inhibit new targets. Alkyl acetylphosphonates (alkyl APs), which inhibit the enzyme 1-deoxy-d-xylulose 5-phosphate synthase (DXPS), represent a new possible class of compounds as there are no FDA-approved DXPS inhibitors. To our knowledge, this is the first study demonstrating the in vivo safety, pharmacokinetics, and efficacy of alkyl APs in a urinary tract infection mouse model.

Combined functional genomic and metabolomic approaches identify new genes required for growth in human urine by multidrug-resistant Escherichia coli ST131.

Uropathogenic Escherichia coli (UPEC) cause ~80% of all urinary tract infections (UTIs), with increasing rates of antibiotic resistance presenting an urgent threat to effective treatment. To cause infection, UPEC must grow efficiently in human urine (HU), necessitating a need to understand mechanisms that promote its adaptation and survival in this nutrient-limited environment. Here, we used a combination of functional genomic and metabolomic techniques and identified roles for the metabolism of small peptides, amino acids, nucleotides, and L-lactate, as well as the stringent response pathway, lipopolysaccharide biosynthesis, and fluoride resistance, for UPEC growth in HU. We further demonstrated that pathways involving nucleotide metabolism and the stringent response are required for UPEC colonization of the mouse bladder. The UPEC genes and metabolic pathways identified in this study represent targets for the development of innovative therapeutics to prevent UPEC growth during human UTI, an urgent need given the rapidly rising rates of global antibiotic resistance.

Secretory leukocyte protease inhibitor protects against severe urinary tract infection in mice.

Millions suffer from urinary tract infections (UTIs) worldwide every year with women accounting for the majority of cases. Uropathogenic Escherichia coli (UPEC) causes most of these primary infections and leads to 25% becoming recurrent or chronic. To repel invading pathogens, the urinary tract mounts a vigorous innate immune response that includes the secretion of antimicrobial peptides (AMPs), rapid recruitment of phagocytes, and exfoliation of superficial umbrella cells. Here, we investigate secretory leukocyte protease inhibitor (SLPI), an AMP with antiprotease, antimicrobial, and immunomodulatory functions, known to play protective roles at other mucosal sites, but not well characterized in UTIs. Using a preclinical model of UPEC-caused UTI, we show that urine SLPI increases in infected mice and that SLPI is localized to bladder epithelial cells. UPEC-infected SLPI-deficient (Slpi-/-) mice suffer from higher urine bacterial burdens, prolonged bladder inflammation, and elevated urine neutrophil elastase (NE) levels compared to wild-type (Slpi+/+) controls. Combined with bulk bladder RNA sequencing, our data indicate that Slpi-/- mice have a dysregulated immune and tissue repair response following UTI. We also measure SLPI in urine samples from a small group of female subjects 18-49 years old and find that SLPI tends to be higher in the presence of a uropathogen, except in patients with a history of recent or recurrent UTI, suggesting a dysregulation of SLPI expression in these women. Taken together, our findings show SLPI promotes clearance of UPEC in mice and provides preliminary evidence that SLPI is likewise regulated in response to uropathogen exposure in women.IMPORTANCEAnnually, millions of people suffer from urinary tract infections (UTIs) and more than $3 billion are spent on work absences and treatment of these patients. While the early response to UTI is known to be important in combating urinary pathogens, knowledge of host factors that help curb infection is still limited. Here, we use a preclinical model of UTI to study secretory leukocyte protease inhibitor (SLPI), an antimicrobial protein, to determine how it protects the bladder against infection. We find that SLPI is increased during UTI, accelerates the clearance of bacteriuria, and upregulates genes and pathways needed to fight an infection while preventing prolonged bladder inflammation. In a small clinical study, we show SLPI is readily detectable in human urine and is associated with the presence of a uropathogen in patients without a previous history of UTI, suggesting SLPI may play an important role in protecting from bacterial cystitis.

Pharmacokinetic and pharmacodynamic evaluation of the atypical tetracyclines chelocardin and amidochelocardin in murine infection models.

There is a strong need to find novel treatment options against urinary tract infections associated with antimicrobial resistance. This study evaluates two atypical tetracyclines, namely chelocardin (CHD) and amidochelocardin (CDCHD), with respect to their pharmacokinetics and pharmacodynamics. We show CHD and CDCHD are cleared at high concentrations in mouse urine. Especially, CDCHD is highly effective in an ascending urinary tract infection model, suggesting further preclinical evaluation.

Hydrogel coatings on universal medical devices with water-responsive Janus adhesion and acidity-triggered transformation for adaptive antibacterial treatment and fluorescence diagnosis

Hydrogel coatings of catheters have attracted extensive attention in the field of medical devices due to its hydrophilicity and softness, while scarcities of Janus adhesion, adaptive antibacterial property, and real-time disease monitoring restricted their clinical translational applications. Herein, a novel hydrogel coating with water-responsive Janus adhesion and acidity-triggered transformation was fabricated for antibacterial treatment and fluorescence diagnosis of catheters-associated infections. First, a sufficient adhesion strength of 44.6 ± 1.9 kPa effectively prevented shedding of the hydrogel coating during catheterization, and meanwhile a super-lubricated layer with an extremely-low coefficient of friction of about 0.03 was formed to reduce friction pain in an aqueous microenvironment. Furthermore, size and fluorescence intensity of chitosan/bovine serum albumin-gold nanoparticles within the hydrogel were varied with pH due to acidity-triggered transformation, where an adaptive release of antibacterial nanoparticles was achieved to reduce biofilms formation and alleviate inflammation degree synergistically. More importantly, such antibacterial treatment was monitored in real-time dependent on an on–off variation of fluorescence intensity. Overall, amounts of in-vitro and in-vivo results performed in rabbit urinary tract infection model and porcine tracheal intubation model fully suggested our newly-synthesized hydrogel coating on universal medical devices showed a promising potential for integrated diagnosis and treatment of catheters-associated infections.

Therapeutic effects of orally administration of viable and inactivated probiotic strains against murine urinary tract infection.

Urinary tract infections (UTIs) are highly prevalent bacterial infections that pose significant health risks. Specific probiotic strains have been recommended for UTI control and management of antibiotic resistance. Otherwise, para-probiotics, defined as inactivated probiotic cells, offer potential advantages by minimizing risks associated with live microorganisms. However, the effectiveness of heat-killed probiotic strains against UTIs remains uncertain. Additionally, lactoferrin (LF), an iron-binding glycoprotein, exhibits immunomodulatory, antimicrobial, and anti-inflammatory properties. Recently, we had developed recombinant LF-expression probiotics, which can display considerate antibacterial activities against select food-borne pathogens in vitro. Thus, the present study aimed to evaluate the antibacterial activities of heat-killed natural and recombinant LF-expressing probiotics against UTIs in vitro and in vivo. Firstly, using in vitro assays, we assessed the antibacterial activity of heat-killed natural and recombinant LF-expressing probiotics against uropathogenic Escherichia coli and Klebsiella pneumoniae. Among the tested probiotics, 10 heat-killed LF-expressing strains displayed superior antibacterial efficacy compared to 12 natural probiotics. Based on their potent in vitro activity, selected probiotics were formulated into three probiotic mixtures: viable probiotic mixture (LAB), heat-killed probiotic mixture (HK-LAB), and heat-killed LF-expressing probiotic mixture (HK-LAB/LF). To further evaluate the therapeutic potential of these probiotic mixtures in vivo, we established a murine model of UTIs by intraurethral administration of E. coli to 40 female C57BL/6JNarl mice on day 0. Subsequently, mice received oral gavage of placebo, LAB, HK-LAB, or HK-LAB/LF for 21 consecutive days (n = 8 per group). An additional control group (n = 8) received ampicillin treatment for 7 days. To assess protective effects against re-infection or UTI relapse, all mice were challenged with E. coli on day 22 and E. coli plus K. pneumoniae on day 25. Results from the murine UTI model demonstrated that placebo administration did not reduce bacteriuria throughout the experiment. Conversely, supplementation with ampicillin, HK-LAB/LF, HK-LAB, or LAB significantly (p < 0.05) reduced daily bacteriuria by 103 to 104-fold on days 1, 3, 5, and 14, respectively. Furthermore, all four therapeutic treatments improved the bacteriological cure rate (BCR) with varying levels of efficacy. For the 7-day treatment course, the BCR was 25% (placebo), 62.5% (ampicillin), 37.5% (LAB), 37.5% (HK-LAB), and 62.5% (HK-LAB/LF). For the 21-day treatment course, the BCR was 25% (placebo), 75% (ampicillin), 37.5% (LAB), 37.5% (HK-LAB), and 75% (HK-LAB/LF). Notably, HK-LAB and HK-LAB/LF demonstrated superior therapeutic efficacy compared to viable LAB in treating UTIs. Overall, regarding BCR, the three probiotic mixtures can provide benefits against UTI in mice, but ampicillin therapy remains the most efficient among the four treatments. Furthermore, there was no significant difference between pre- and post-challenge courses for the two instances of re-challenging uropathogens in all mice groups, as bacteriuria levels remained below 103 CFU/mL, implying that adaptive responses of mice may help reduce the risk of recurrent UTIs. In conclusion, our results provide new evidence that oral administration of heat-killed probiotic mixtures can confer significant therapeutic efficacy against UTIs in a murine model.

Raising the alarm: fosfomycin resistance associated with non-susceptible inner colonies imparts no fitness cost to the primary bacterial uropathogen.

While fosfomycin resistance is rare, the observation of non-susceptible subpopulations among clinical Escherichia coli isolates is a common phenomenon during antimicrobial susceptibility testing (AST) in American and European clinical labs. Previous evidence suggests that mutations eliciting this phenotype are of high biological cost to the pathogen during infection, leading to current recommendations of neglecting non-susceptible colonies during AST. Here, we report that the most common route to fosfomycin resistance, as well as novel routes described in this work, does not impair virulence in uropathogenic E. coli, the major cause of urinary tract infections, suggesting a re-evaluation of current susceptibility guidelines is warranted.

Characterization of the Entner-Doudoroff pathway in Pseudomonas aeruginosa catheter-associated urinary tract infections.

Pseudomonas aeruginosa is an opportunistic nosocomial pathogen responsible for a subset of catheter-associated urinary tract infections (CAUTI). In a murine model of P. aeruginosa CAUTI, we previously demonstrated that urea within urine suppresses quorum sensing and induces the Entner-Doudoroff (E-D) pathway. The E-D pathway consists of the genes zwf, pgl, edd, and eda. Zwf and Pgl convert glucose-6-phosphate into 6-phosphogluconate. Edd hydrolyzes 6-phosphogluconate to 2-keto-3-deoxy-6-phosphogluconate (KDPG). Finally, Eda cleaves KDPG to glyceraldehyde-3-phosphate and pyruvate, which enters the citric acid cycle. Here, we generated in-frame E-D mutants in the strain PA14 and assessed their growth phenotypes on chemically defined and complex media. These E-D mutants have a growth defect when grown on glucose or gluconate as the sole carbon source, which is similar to results previously reported for PAO1 mutants lacking E-D genes. RNA-sequencing following short exposure to urine revealed minimal gene regulation differences compared to the wild type. In a murine CAUTI model, virulence testing of E-D mutants revealed that two mutants lacking zwf and pgl showed minor fitness defects. Infection with the ∆pgl strain exhibited a 20% increase in host survival, and the ∆zwf strain displayed decreased colonization of the catheter and kidneys. Consequently, our findings suggest that the E-D pathway in P. aeruginosa is dispensable in this model of CAUTI. IMPORTANCE Prior studies have shown that the Entner-Doudoroff pathway is up-regulated when Pseudomonas aeruginosa is grown in urine. Pseudomonads use the Entner-Doudoroff (E-D) pathway to metabolize glucose instead of glycolysis, which led us to ask whether this pathway is required for urinary tract infection. Here, single-deletion mutants of each gene in the pathway were tested for growth on chemically defined media with single-carbon sources as well as complex media. The effect of each mutant on global gene expression in laboratory media and urine was characterized. The virulence of these mutants in a murine model of catheter-associated urinary tract infection revealed that these mutants had similar levels of colonization indicating that glucose is not the primary carbon source utilized in the urinary tract.

Antibacterial activity of methanolic crude extracts from Aerva lanata (L.) A.L. Juss. ex Schultes against Staphylococcus aureus and Escherichia coli using in vitro bladder model for catheter-associated urinary tract infection

Antibacterial activity of methanolic crude extracts from Aerva lanata (L.) A.L. Juss. ex Schultes against Staphylococcus aureus and Escherichia coli using in vitro bladder model for catheter-associated urinary tract infection

Establishment of a Urinary Tract Infection Model in Female Mice

Establishment of a Urinary Tract Infection Model in Female Mice

Transurethral Catheterization and Bacterial Inoculation to Generate a Urinary Tract Infection Model in Male Mice

Transurethral Catheterization and Bacterial Inoculation to Generate a Urinary Tract Infection Model in Male Mice

Establishment of a Urinary Tract Infection Model in Female Mice

Establishment of a Urinary Tract Infection Model in Female Mice

Transurethral Catheterization and Bacterial Inoculation to Generate a Urinary Tract Infection Model in Male Mice

Transurethral Catheterization and Bacterial Inoculation to Generate a Urinary Tract Infection Model in Male Mice

Preoperative Prediction of Postoperative Infections Using Machine Learning and Electronic Health Record Data.

To estimate preoperative risk of postoperative infections using structured electronic health record (EHR) data. Surveillance and reporting of postoperative infections is primarily done through costly, labor-intensive manual chart reviews on a small sample of patients. Automated methods using statistical models applied to postoperative EHR data have shown promise to augment manual review as they can cover all operations in a timely manner. However, there are no specific models for risk-adjusting infectious complication rates using EHR data. Preoperative EHR data from 30,639 patients (2013-2019) were linked to the American College of Surgeons National Surgical Quality Improvement Program preoperative data and postoperative infection outcomes data from 5 hospitals in the University of Colorado Health System. EHR data included diagnoses, procedures, operative variables, patient characteristics, and medications. Lasso and the knockoff filter were used to perform controlled variable selection. Outcomes included surgical site infection, urinary tract infection, sepsis/septic shock, and pneumonia up to 30 days postoperatively. Among >15,000 candidate predictors, 7 were chosen for the surgical site infection model and 6 for each of the urinary tract infection, sepsis, and pneumonia models. Important variables included preoperative presence of the specific outcome, wound classification, comorbidities, and American Society of Anesthesiologists physical status classification. The area under the receiver operating characteristic curve for each model ranged from 0.73 to 0.89. Parsimonious preoperative models for predicting postoperative infection risk using EHR data were developed and showed comparable performance to existing American College of Surgeons National Surgical Quality Improvement Program risk models that use manual chart review. These models can be used to estimate risk-adjusted postoperative infection rates applied to large volumes of EHR data in a timely manner.

Development of a risk nomogram predicting urinary tract infection in patients with indwelling urinary catheter after radical surgery for cervical cancer.

Cervical cancer (CC) patients receiving indwelling catheterization after radical hysterectomy (RH) are vulnerable to urinary tract infection (UTI). However, no model or method is available to predict the risk of UTIs. Therefore, our aim was to develop and verify a risk model to predict UTI for patients receiving indwelling catheterization after radical cervical cancer surgery (ICa-RCCS). We first collected clinical information of 380 patients receiving ICa-RCCS from January 2020 to December 2021 as a training cohort to develop the risk nomogram. UTI was then evaluated using 19UTI predictor factors. The least absolute shrinkage and selection operator (LASSO) method was utilized for the extraction characteristics. Multivariable logistic regression analysis was then conducted to create the risk model for UTI prediction. The consistency coefficient and calibration curve were utilized to assess the model's fit accuracy. We performed bootstrapping with 1000random samples for internal validation of the model, and decision curve analysis (DCA) for clinical application. Predictors in the risk nomogram included indwelling catheterization duration, whether it is secondary indwelling catheterization, history of UTIs, age, and history of chemotherapy before surgery. The risk nomogram presented good discrimination and calibration (C-index: 0.810, 95% CI: 0.759-0.861). During interval validation, the model reached a high C-index up to 0.7930. DCA revealed the clinical utility of predictive model for UTI. Clinical benefit was initiated at the decision threshold≥3%. We developed a novel UTI nomogram incorporating the age, history of chemotherapy before surgery, indwelling catheterization duration, whether it is secondary indwelling catheterization, and history of UTI to predict UTI risk for patients receiving ICa-RCCS. B: 3a.

Study of the uroantiseptic activity of the complex of glycosides of phenolic compounds from lingonberry leaves in complex with the arginine amino acid

The aim of the work – study the uroantiseptic activity of a complex of glycosides of phenolic compounds from lingonberry leaves in a complex with the amino acid arginine.&#x0D; Materials and methods. The object of the study was a phytosubstance, which is a complex of glycosides of phenolic compounds from lingonberry leaves in combination with the amino acid arginine (CGPA). Female laboratory rats were given a cleansing enema twice, after which the rats were provided with adequate sedation by injecting IV XYLA 2 % for anesthesia, then rectally injected 1000 μl of Escherichia coli strain at a concentration of 109 CFU/ml. The next day after infection, the animals were subjected to cryogenic action - acute cold stress at a temperature of 0+2 °C for 2.5 hours, promoting the development of the infectious and inflammatory process. The uroantiseptic effect was studied according to the following parameters: the number of leukocytes in the urine, the number of colony-forming microorganisms E.coli in 1 ml of urine (CFU/ml).&#x0D; Results. According to the obtained results of the experiment, it was established that the complex of glycosides of phenolic compounds from the leaves of lingonberry in a complex with the amino acid arginine (CGPA) showed a high uroantiseptic effect in the experimental treatment of urinary tract infection caused by E. coli ATCC 25922, which was manifested in the sanitation of the urinary tract from the uropathogen E. Coli.&#x0D; Conclusions. Analyzing the results, it can be concluded that on the model of urinary tract infection against the background of cryogenic exposure, CGPA at a dose of 100 mg/kg showed a uroantiseptic effect, which was stronger than the comparison drug "Inurek" and contributed to a faster disappearance of the titer of colony-forming microorganisms in 1 ml of urine about 2 days earlier than in the group that received dietary supplements of herbal origin "Inurek" and the disappearance of leukocyturia 3 days earlier compared to the group that received therapy with the comparison drug "Inurek". The obtained results indicate the prospects of further research of CGPA with the aim of creating new effective uroantiseptic agents of plant origin based on it

Preclinical safety and efficacy characterization of an LpxC inhibitor against Gram-negative pathogens.

The UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase LpxC is an essential enzyme in the biosynthesis of lipid A, the outer membrane anchor of lipopolysaccharide and lipooligosaccharide in Gram-negative bacteria. The development of LpxC-targeting antibiotics toward clinical therapeutics has been hindered by the limited antibiotic profile of reported non-hydroxamate inhibitors and unexpected cardiovascular toxicity observed in certain hydroxamate and non-hydroxamate-based inhibitors. Here, we report the preclinical characterization of a slow, tight-binding LpxC inhibitor, LPC-233, with low picomolar affinity. The compound is a rapid bactericidal antibiotic, unaffected by established resistance mechanisms to commercial antibiotics, and displays outstanding activity against a wide range of Gram-negative clinical isolates in vitro. It is orally bioavailable and efficiently eliminates infections caused by susceptible and multidrug-resistant Gram-negative bacterial pathogens in murine soft tissue, sepsis, and urinary tract infection models. It displays exceptional in vitro and in vivo safety profiles, with no detectable adverse cardiovascular toxicity in dogs at 100 milligrams per kilogram. These results establish the feasibility of developing oral LpxC-targeting antibiotics for clinical applications.

Defining the Roles of Pyruvate Oxidation, TCA Cycle, and Mannitol Metabolism in Methicillin-Resistant Staphylococcus aureus Catheter-Associated Urinary Tract Infection.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of complicated urinary tract infection (UTI) associated with the use of indwelling urinary catheters. Previous reports have revealed host and pathogen effectors critical for MRSA uropathogenesis. Here, we sought to determine the significance of specific metabolic pathways during MRSA UTI. First, we identified four mutants from the Nebraska transposon mutant library in the MRSA JE2 background that grew normally in rich medium but displayed significantly reduced growth in pooled human urine (HU). This prompted us to transduce the uropathogenic MRSA 1369 strain with the transposon mutants in sucD and fumC (tricarboxylic acid [TCA] cycle), mtlD (mannitol metabolism), and lpdA (pyruvate oxidation). Notably, sucD, fumC, and mtlD were also significantly upregulated in the MRSA 1369 strain upon exposure to HU. Compared to the WT, the MRSA 1369 lpdA mutant was significantly defective for (i) growth in HU, and (ii) colonization of the urinary tract and dissemination to the kidneys and the spleen in the mouse model of catheter-associated UTI (CAUTI), which may be attributed to its increased membrane hydrophobicity and higher susceptibility to killing by human blood. In contrast to their counterparts in the JE2 background, the sucD, fumC, and mtlD mutants in the MRSA 1369 background grew normally in HU; however, they displayed significant fitness defects in the CAUTI mouse model. Overall, identification of novel metabolic pathways important for the urinary fitness and survival of MRSA can be used for the development of novel therapeutics. IMPORTANCE While Staphylococcus aureus has historically not been considered a uropathogen, S. aureus urinary tract infection (UTI) is clinically significant in certain patient populations, including those with chronic indwelling urinary catheters. Moreover, most S. aureus strains causing catheter-associated UTI (CAUTI) are methicillin-resistant S. aureus (MRSA). MRSA is difficult to treat due to limited treatment options and the potential to deteriorate into life-threatening bacteremia, urosepsis, and shock. In this study, we found that pathways involved in pyruvate oxidation, TCA cycle, and mannitol metabolism are important for MRSA fitness and survival in the urinary tract. Improved understanding of the metabolic needs of MRSA in the urinary tract may help us develop novel inhibitors of MRSA metabolism that can be used to treat MRSA-CAUTI more effectively.

Dynamics of Urinary Extracellular DNA in Urosepsis.

Extracellular DNA (ecDNA) is a promising candidate marker for the early diagnosis and monitoring of urinary tract infections (UTIs). The aim of our study is to describe the dynamics of ecDNA in the plasma and urine of patients with urosepsis as well as in a mouse model of UTI. Samples of blood and urine were collected from adult patients with UTIs and obstructive uropathy (n = 36) during the first 3 days at the hospital and during a follow-up. Bacterial burden and urinary ecDNA were evaluated in a mouse UTI model (n = 26) at baseline; 24, 48, and 72 h after UTI induction; and 7 days after UTI induction. The plasma ecDNA did not change during urosepsis, but the plasma DNase activity increased significantly at the follow-up. The urinary ecDNA decreased significantly during hospitalization and remained low until the follow-up (90% lower vs. admission). No change was seen in the urinary DNase activity. C-reactive protein (CRP) and procalcitonin are positively correlated with plasma and urinary ecDNA. A UTI caused sepsis in 23% of mice. The urinary ecDNA decreased by three-fold and remained low until day 7 post-infection. Urinary bacterial burden is correlated with urinary ecDNA. Urinary ecDNA is a potential non-invasive marker for monitoring the effects of treatment during urosepsis and is related to UTI progression in the experimental animal model.

Antibacterial and Analgesic Properties of Beta-Caryophyllene in a Murine Urinary Tract Infection Model.

Beta-caryophyllene has demonstrated anti-inflammatory effects in a variety of conditions, including interstitial cystitis. These effects are mediated primarily via the activation of the cannabinoid type 2 receptor. Additional antibacterial properties have recently been suggested, leading to our investigation of the effects of beta-caryophyllene in a murine model of urinary tract infection (UTI). Female BALB/c mice were intravesically inoculated with uropathogenic Escherichia coli CFT073. The mice received either beta-caryophyllene, antibiotic treatment using fosfomycin, or combination therapy. After 6, 24, or 72 h, the mice were evaluated for bacterial burden in the bladder and changes in pain and behavioral responses using von Frey esthesiometry. In the 24 h model, the anti-inflammatory effects of beta-caryophyllene were also assessed using intravital microscopy. The mice established a robust UTI by 24 h. Altered behavioral responses persisted 72 h post infection. Treatment with beta-caryophyllene resulted in a significant reduction in the bacterial burden in urine and bladder tissues 24 h post UTI induction and significant improvements in behavioral responses and intravital microscopy parameters, representing reduced inflammation in the bladder. This study demonstrates the utility of beta-caryophyllene as a new adjunct therapy for the management of UTI.