scholarly journals The Two-Component System GrvRS (EtaRS) RegulatesaceExpression in Enterococcus faecalis OG1RF

2014 ◽  
Vol 83 (1) ◽  
pp. 389-395 ◽  
Author(s):  
Jung Hyeob Roh ◽  
Kavindra V. Singh ◽  
Sabina Leanti La Rosa ◽  
Ana Luisa V. Cohen ◽  
Barbara E. Murray
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Regulatory System ◽  
Northern Hybridization ◽  
Infection Model ◽  
Content Type ◽  
Infection Models ◽  
Two Component ◽  
Main Regulator

Expression oface(adhesin tocollagen ofEnterococcus faecalis), encoding a virulence factor in endocarditis and urinary tract infection models, has been shown to increase under certain conditions, such as in the presence of serum, bile salts, urine, and collagen and at 46°C. However, the mechanism oface/Ace regulation under different conditions is still unknown. In this study, we identified a two-component regulatory system GrvRS as the main regulator ofaceexpression under these stress conditions. Using Northern hybridization and β-galactosidase assays of anacepromoter-lacZfusion, we found transcription ofaceto be virtually absent in agrvRdeletion mutant under the conditions that increaseaceexpression in wild-type OG1RF and in the complemented strain. Moreover, agrvRmutant revealed decreased collagen binding and biofilm formation as well as attenuation in a murine urinary tract infection model. Here we show that GrvR plays a major role in control ofaceexpression andE. faecalisvirulence.

scholarly journals Efficacy of Ceftobiprole Medocaril against Enterococcus faecalis in a Murine Urinary Tract Infection Model

2012 ◽  
Vol 56 (6) ◽  
pp. 3457-3460 ◽  
Author(s):  
Kavindra V. Singh ◽  
Barbara E. Murray
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Enterococcus Faecalis ◽  
Infection Model ◽  
Content Type ◽  
The Stability

ABSTRACTWe evaluated ceftobiprole against the well-characterizedEnterococcus faecalisstrain OG1RF (with and without the β-lactamase [Bla] plasmid pBEM10) in a murine urinary tract infection (UTI) model. Ceftobiprole was equally effective for Bla+and Bla−OG1 strains, while ampicillin was moderately to markedly (depending on the inoculum) less effective against Bla+than Bla−OG1 strains. These data illustrate anin vivoeffect on ampicillin of Bla production byE. faecalisand the stability and efficacy of ceftobiprole in experimental UTI.

scholarly journals Ciprofloxacin Pharmacokinetics/Pharmacodynamics against Susceptible and Low-Level Resistant Escherichia coli Isolates in an Experimental Ascending Urinary Tract Infection Model in Mice

2020 ◽  
Vol 65 (1) ◽  
pp. e01804-20
Author(s):  
Lotte Jakobsen ◽  
Carina Vingsbro Lundberg ◽  
Niels Frimodt-Møller
Keyword(s):  
Escherichia Coli ◽  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Infection Model ◽  
Bladder Tissue ◽  
Content Type ◽  
E Coli ◽  
Low Level ◽  
Level Resistance

ABSTRACTThe mouse ascending urinary tract infection model was used to study the pharmacokinetic/pharmacodynamic (PKPD) relationships of the effect of ciprofloxacin in subcutaneous treatment for 3 days with varying doses and dosing intervals against a susceptible Escherichia coli strain (MIC, 0.032 mg/liter). Further, a humanized dose of ciprofloxacin was administered for 3 days against three E. coli strains with low-level resistance, i.e., MICs of 0.06, 0.25, and 1 mg/liter, respectively. Against the susceptible isolate, ciprofloxacin was highly effective in clearing the urine with daily doses from 10 mg/kg, but the dosing regimen had to be divided into at least two doses for optimal effect. Ciprofloxacin could not clear the urine or kidneys for the low-level-resistant strains. PKPD correlations with all strains combined showed that for the AUC24/MIC there was a slightly higher correlation with effect in urine and kidneys (R2, 0.71 and 0.69, respectively) than the %T>MIC (R2, 0.41 and 0.61, respectively). Equal correlations for the two PKPD indices were found for reduction of colony counts (CFU) in the bladder tissue, but not even the highest dose of 28 mg/kg × 6 could clear the bladder tissue. In conclusion, ciprofloxacin is highly effective in clearing the urine and kidney tissue for fully susceptible E. coli, while even low-level resistance in E. coli obscures this effect. While the effect of ciprofloxacin is mostly AUC/MIC driven against E. coli infection in the urinary tract, the effect in urine depends on the presence of ciprofloxacin in the urine during most of a 24-h period.

scholarly journals Synchrotron X-Ray Fluorescence Microscopy of Gallium in Bladder Tissue following Gallium Maltolate Administration during Urinary Tract Infection

2013 ◽  
Vol 57 (11) ◽  
pp. 5197-5201 ◽  
Author(s):  
Katherine R. Ball ◽  
Francesca Sampieri ◽  
Manuel Chirino ◽  
Don L. Hamilton ◽  
Robert I. R. Blyth ◽  
...  
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Transitional Epithelium ◽  
Bladder Tissue ◽  
Content Type ◽  
X Ray ◽  
E Coli ◽  
Tract Infections ◽  
X Ray Absorption

ABSTRACTA mouse model of cystitis caused by uropathogenicEscherichia coliwas used to study the distribution of gallium in bladder tissue following oral administration of gallium maltolate during urinary tract infection. The median concentration of gallium in homogenized bladder tissue from infected mice was 1.93 μg/g after daily administration of gallium maltolate for 5 days. Synchrotron X-ray fluorescence imaging and X-ray absorption spectroscopy of bladder sections confirmed that gallium arrived at the transitional epithelium, a potential site of uropathogenicE. coliinfection. Gallium and iron were similarly but not identically distributed in the tissues, suggesting that at least some distribution mechanisms are not common between the two elements. The results of this study indicate that gallium maltolate may be a suitable candidate for further development as a novel antimicrobial therapy for urinary tract infections caused by uropathogenicE. coli.

scholarly journals Complete Genome Sequences of Three Lactobacillus crispatus Strains Isolated from the Urine of Postmenopausal Women

2021 ◽  
Vol 10 (48) ◽  
Author(s):  
Neha V. Hulyalkar ◽  
Belle M. Sharon ◽  
Braden M. Shipman ◽  
Amanda P. Arute ◽  
Philippe E. Zimmern ◽  
...  
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Postmenopausal Women ◽  
Complete Genome ◽  
Genome Sequences ◽  
Content Type ◽  
Lactobacillus Crispatus ◽  
Healthy Women ◽  
Vaginal Health

Lactobacillus crispatus frequently colonizes the vagina and bladder of healthy women. Although its association with vaginal health is relatively well understood, little is known about its role in urinary tract infection (UTI). Here, we report the complete genome sequences of three urinary L. crispatus strains isolated from women with different UTI histories.

scholarly journals The Pathogenic Potential of Proteus mirabilis Is Enhanced by Other Uropathogens during Polymicrobial Urinary Tract Infection

2016 ◽  
Vol 85 (2) ◽  
Author(s):  
Chelsie E. Armbruster ◽  
Sara N. Smith ◽  
Alexandra O. Johnson ◽  
Valerie DeOrnellas ◽  
Kathryn A. Eaton ◽  
...  
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Disease Severity ◽  
Proteus Mirabilis ◽  
Tissue Damage ◽  
Urease Activity ◽  
Pathogenic Potential ◽  
Content Type

ABSTRACT Urinary catheter use is prevalent in health care settings, and polymicrobial colonization by urease-positive organisms, such as Proteus mirabilis and Providencia stuartii, commonly occurs with long-term catheterization. We previously demonstrated that coinfection with P. mirabilis and P. stuartii increased overall urease activity in vitro and disease severity in a model of urinary tract infection (UTI). In this study, we expanded these findings to a murine model of catheter-associated UTI (CAUTI), delineated the contribution of enhanced urease activity to coinfection pathogenesis, and screened for enhanced urease activity with other common CAUTI pathogens. In the UTI model, mice coinfected with the two species exhibited higher urine pH values, urolithiasis, bacteremia, and more pronounced tissue damage and inflammation compared to the findings for mice infected with a single species, despite having a similar bacterial burden within the urinary tract. The presence of P. stuartii, regardless of urease production by this organism, was sufficient to enhance P. mirabilis urease activity and increase disease severity, and enhanced urease activity was the predominant factor driving tissue damage and the dissemination of both organisms to the bloodstream during coinfection. These findings were largely recapitulated in the CAUTI model. Other uropathogens also enhanced P. mirabilis urease activity in vitro, including recent clinical isolates of Escherichia coli, Enterococcus faecalis, Klebsiella pneumoniae, and Pseudomonas aeruginosa. We therefore conclude that the underlying mechanism of enhanced urease activity may represent a widespread target for limiting the detrimental consequences of polymicrobial catheter colonization, particularly by P. mirabilis and other urease-positive bacteria.

scholarly journals Complete Genome Sequences of Seven Uropathogenic Escherichia coli Strains Isolated from Postmenopausal Women with Recurrent Urinary Tract Infection

2020 ◽  
Vol 9 (33) ◽  
Author(s):  
Belle M. Sharon ◽  
Amber Nguyen ◽  
Amanda P. Arute ◽  
Neha V. Hulyalkar ◽  
Vivian H. Nguyen ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Postmenopausal Women ◽  
Complete Genome ◽  
Recurrent Urinary Tract Infection ◽  
Uropathogenic Escherichia Coli ◽  
Genome Sequences ◽  
Content Type

ABSTRACT Uropathogenic Escherichia coli (UPEC) is the most common cause of urinary tract infection (UTI). This disease disproportionately affects women and frequently develops into recurrent UTI (rUTI) in postmenopausal women. Here, we report the complete genome sequences of seven UPEC isolates obtained from the urine of postmenopausal women with rUTI.

scholarly journals (p)ppGpp and CodY Promote Enterococcus faecalis Virulence in a Murine Model of Catheter-Associated Urinary Tract Infection

mSphere ◽  
2019 ◽  
Vol 4 (4) ◽  
Author(s):  
C. Colomer-Winter ◽  
A. L. Flores-Mireles ◽  
S. Kundra ◽  
S. J. Hultgren ◽  
J. A. Lemos
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Enterococcus Faecalis ◽  
Stringent Response ◽  
Nutrient Sensing ◽  
Transcriptional Analysis ◽  
Content Type ◽  
Tract Infections

ABSTRACT In Firmicutes, the nutrient-sensing regulators (p)ppGpp, the effector molecule of the stringent response, and CodY work in tandem to maintain bacterial fitness during infection. Here, we tested (p)ppGpp and codY mutant strains of Enterococcus faecalis in a catheter-associated urinary tract infection (CAUTI) mouse model and used global transcriptional analysis to investigate the relationship of (p)ppGpp and CodY. The absence of (p)ppGpp or single inactivation of codY led to lower bacterial loads in catheterized bladders and diminished biofilm formation on fibrinogen-coated surfaces under in vitro and in vivo conditions. Single inactivation of the bifunctional (p)ppGpp synthetase/hydrolase rel did not affect virulence, supporting previous evidence that the association of (p)ppGpp with enterococcal virulence is not dependent on the activation of the stringent response. Inactivation of codY in the (p)ppGpp0 strain restored E. faecalis virulence in the CAUTI model as well as the ability to form biofilms in vitro. Transcriptome analysis revealed that inactivation of codY restores, for the most part, the dysregulated metabolism of (p)ppGpp0 cells. While a clear linkage between (p)ppGpp and CodY with expression of virulence factors could not be established, targeted transcriptional analysis indicates that a possible association between (p)ppGpp and c-di-AMP signaling pathways in response to the conditions found in the bladder may play a role in enterococcal CAUTI. Collectively, data from this study identify the (p)ppGpp-CodY network as an important contributor to enterococcal virulence in catheterized mouse bladder and support that basal (p)ppGpp pools and CodY promote virulence through maintenance of a balanced metabolism under adverse conditions. IMPORTANCE Catheter-associated urinary tract infections (CAUTIs) are one of the most frequent types of infection found in the hospital setting that can develop into serious and potentially fatal bloodstream infections. One of the infectious agents that frequently causes complicated CAUTI is the bacterium Enterococcus faecalis, a leading cause of hospital-acquired infections that are often difficult to treat due to the exceptional multidrug resistance of some isolates. Understanding the mechanisms by which E. faecalis causes CAUTI will aid in the discovery of new druggable targets to treat these infections. In this study, we report the importance of two nutrient-sensing bacterial regulators, named (p)ppGpp and CodY, for the ability of E. faecalis to infect the catheterized bladder of mice.

scholarly journals Copper Is a Host Effector Mobilized to Urine during Urinary Tract Infection To Impair Bacterial Colonization

2016 ◽  
Vol 85 (3) ◽  
Author(s):  
Amanda N. Hyre ◽  
Kylie Kavanagh ◽  
Nancy D. Kock ◽  
George L. Donati ◽  
Sargurunathan Subashchandrabose
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Bacterial Growth ◽  
Bacterial Colonization ◽  
Content Type ◽  
Cu Content ◽  
Novel Approach ◽  
Urinary Copper ◽  
Pathogen Colonization

ABSTRACT Urinary tract infection (UTI) is a major global infectious disease affecting millions of people annually. Human urinary copper (Cu) content is elevated during UTI caused by uropathogenic Escherichia coli (UPEC). UPEC upregulates the expression of Cu efflux genes during clinical UTI in patients as an adaptive response to host-derived Cu. Whether Cu is mobilized to urine as a host response to UTI and its role in protection against UTI remain unresolved. To address these questions, we tested the hypothesis that Cu is a host effector mobilized to urine during UTI to limit bacterial growth. Our results reveal that Cu is mobilized to urine during UTI caused by the major uropathogens Proteus mirabilis and Klebsiella pneumoniae, in addition to UPEC, in humans. Ceruloplasmin, a Cu-containing ferroxidase, is found at higher levels in UTI urine than in healthy control urine and serves as the molecular source of urinary Cu during UTI. Our results demonstrate that ceruloplasmin decreases the bioavailability of iron in urine by a transferrin-dependent mechanism. Experimental UTI with UPEC in nonhuman primates recapitulates the increased urinary Cu content observed during clinical UTI. Furthermore, Cu-deficient mice are highly colonized by UPEC, indicating that Cu is involved in the limiting of bacterial growth within the urinary tract. Collectively, our results indicate that Cu is a host effector that is involved in protection against pathogen colonization of the urinary tract. Because urinary Cu levels are amenable to modulation, augmentation of the Cu-based host defense against UTI represents a novel approach to limiting bacterial colonization during UTI.

scholarly journals Role of Ethanolamine Utilization Genes in Host Colonization during Urinary Tract Infection

2017 ◽  
Vol 86 (3) ◽  
Author(s):  
Anna Sintsova ◽  
Sara Smith ◽  
Sargurunathan Subashchandrabose ◽  
Harry L. Mobley
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Mouse Model ◽  
Virulence Determinants ◽  
Content Type ◽  
Immunocompromised Mouse ◽  
Common Infection ◽  
Increased Susceptibility

ABSTRACTUrinary tract infection (UTI) is the second most common infection in humans, making it a global health priority. Nearly half of all women will experience a symptomatic UTI, with uropathogenicEscherichia coli(UPEC) being the major causative agent of the infection. Although there has been extensive research on UPEC virulence determinants, the importance of host-specific metabolism remains understudied. We report here that UPEC upregulates the expression of ethanolamine utilization genes during uncomplicated UTIs in humans. We further show that UPEC ethanolamine metabolism is required for effective bladder colonization in the mouse model of ascending UTI and is dispensable for bladder colonization in an immunocompromised mouse model of UTI. We demonstrate that although ethanolamine metabolism mutants do not show increased susceptibility to antimicrobial responses of neutrophils, this metabolic pathway is important for surviving the innate immune system during UTI. This study reveals a novel aspect of UPEC metabolism in the host and provides evidence for an underappreciated link between bacterial metabolism and the host immune response.

scholarly journals A Multicenter, Randomized, Double-Blind, Phase 2 Study of the Efficacy and Safety of Plazomicin Compared with Levofloxacin in the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Lynn E. Connolly ◽  
Valerie Riddle ◽  
Deborah Cebrik ◽  
Eliana S. Armstrong ◽  
Loren G. Miller
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Acute Pyelonephritis ◽  
Complicated Urinary Tract Infection ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Content Type ◽  
Phase 2 Study

ABSTRACTIncreasing antimicrobial resistance among uropathogens limits treatment options for patients with complicated urinary tract infection (cUTI). Plazomicin, a new aminoglycoside, hasin vitroactivity against multidrug-resistantEnterobacteriaceae, including isolates resistant to currently available aminoglycosides, as well as extended-spectrum β-lactamase-producing and carbapenem-resistantEnterobacteriaceae. We evaluated the efficacy and safety of plazomicin in a double-blind, comparator-controlled, phase 2 study in adults with cUTI or acute pyelonephritis. Patients were randomized 1:1:1 to receive intravenous plazomicin (10 or 15 mg/kg of body weight) or intravenous levofloxacin (750 mg) once daily for 5 days. Coprimary efficacy endpoints were microbiological eradication at the test of cure (TOC; 5 to 12 days after the last dose) in the modified intent-to-treat (MITT) and microbiologically evaluable (ME) populations. Overall, 145 patients were randomized to treatment. In the groups receiving plazomicin at 10 mg/kg, plazomicin at 15 mg/kg, and levofloxacin, microbiological eradication rates were, respectively, 50.0% (6 patients with microbiological eradication at TOC/12 patients treated [95% confidence interval {CI}, 21.1 to 78.9%]), 60.8% (31/51 [95% CI, 46.1 to 74.2%]), and 58.6% (17/29 [95% CI, 38.9 to 76.5%]) in the MITT population and 85.7% (6/7 [95% CI, 42.1 to 99.6%]), 88.6% (31/35 [95% CI, 73.3 to 96.8%]), and 81.0% (17/21 [95% CI, 58.1 to 94.6%]) in the ME population. In the MITT population, 66.7% (95% CI, 34.9 to 90.1%), 70.6% (95% CI, 56.2 to 82.5%), and 65.5% (95% CI, 45.7 to 82.1%) of the patients in the three groups, respectively, were assessed by the investigator to be clinically cured at TOC. Adverse events were reported in 31.8%, 35.1%, and 47.7% of the patients in the three groups, respectively. Serum creatinine values were generally stable over the course of the study. No plazomicin-treated patients with evaluable audiometry data had postbaseline sensorineural, conductive, or mixed hearing loss. In summary, plazomicin demonstrated microbiological and clinical success and an overall safety profile supportive of further clinical development. (This study has been registered at ClinicalTrials.gov under identifier NCT01096849.)

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