Next Article in Journal
The Genomic Variation and Differentially Expressed Genes on the 6P Chromosomes in Wheat–Agropyron cristatum Addition Lines 5113 and II-30-5 Confer Different Desirable Traits
Next Article in Special Issue
Effects of Therapeutic Platelet-Rich Plasma on Overactive Bladder via Modulating Hyaluronan Synthesis in Ovariectomized Rat
Previous Article in Journal
Anti-Obesity and Anti-Inflammatory Synergistic Effects of Green Tea Catechins and Citrus β-Cryptoxanthin Ingestion in Obese Mice
Previous Article in Special Issue
Sensory Receptor, Inflammatory, and Apoptotic Protein Expression in the Bladder Urothelium of Patients with Different Subtypes of Interstitial Cystitis/Bladder Pain Syndrome
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 24
Issue 8
10.3390/ijms24087055
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Emerging Non-Antibiotic Options Targeting Uropathogenic Mechanisms for Recurrent Uncomplicated Urinary Tract Infection

by
Yu-Chen Chen
1,2,3,
Wei-Chia Lee
4,* and
Yao-Chi Chuang
4,5
1
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
2
Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
3
Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
4
Division of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
5
Center for Shock Wave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(8), 7055; https://doi.org/10.3390/ijms24087055
Submission received: 26 February 2023 / Revised: 6 April 2023 / Accepted: 9 April 2023 / Published: 11 April 2023
(This article belongs to the Special Issue Pathophysiology and Therapy of Bladder Function Disorders and Cystitis)
Browse Figures
Review Reports Versions Notes

Abstract

:
Urinary tract infections (UTIs) are the most frequent bacterial infections in the clinical setting. Even without underlying anatomic or functional abnormalities, more than 40% of women experience at least one UTI in their lifetime, of which 30% develop recurrent UTIs (rUTIs) within 6 months. Conventional management with antibiotics for rUTIs may eventually lead to the development of multidrug-resistant uropathogens. Targeting of the pathogenicity of rUTIs, the evolution of uropathogenic Escherichia coli (UPEC), and inadequate host defenses by immune responses should be explored to provide non-antibiotic solutions for the management of rUTIs. The adaptive evolution of UPEC has been observed in several aspects, including colonization, attachment, invasion, and intracellular replication to invade the urothelium and survive intracellularly. Focusing on the antivirulence of UPEC and modulating the immunity of susceptible persons, researchers have provided potential alternative solutions in four categories: antiadhesive treatments (i.e., cranberries and D-mannose), immunomodulation therapies, vaccines, and prophylaxis with topical estrogen therapy and probiotics (e.g., Lactobacillus species). Combination therapies targeting multiple pathogenic mechanisms are expected to be a future trend in UTI management, although some of these treatment options have not been well established in terms of their long-term efficacy. Additional clinical trials are warranted to validate the therapeutic efficacy and durability of these techniques.

1. Introduction

Urinary tract infections (UTIs) are the most common bacterial infections in the outpatient setting and occur mainly in women [1]. More than 40% of women experience acute cystitis during their lifetime [2]. Among young women without underlying anatomical or functional abnormalities, 25% experience a recurrence of cystitis within 6 months of the initial UTI. The first-line treatment for uncomplicated UTIs depends on the use of a short-course antimicrobial regimen [3]. However, conventional prophylaxis and treatment of UTIs using antibiotics can result in the long-term alteration of the normal microbiota of the vagina and gastrointestinal tract and in the growth of multidrug-resistant (MDR) microorganisms. From a socioeconomic perspective, recurrent UTIs (rUTIs) may worsen global public health, lead to a high economic burden, and affect the quality of life of women [4].
rUTIs are defined as at least two symptomatic episodes within 6 months or at least three episodes within a period of 1 year. From the viewpoint of pathogenicity, the offending uropathogens and host susceptibility or a combination of both are responsible for the occurrence of rUTIs. Indeed, up to 80% of UTIs are caused by Escherichia coli, which accounts for half of the estimated global antibiotic resistance [5,6]. Therefore, rUTIs may present as either relapsing infections due to an incomplete clearance of uropathogens within two weeks of the treatment course or reinfection, which occurs two weeks after treatment completion. The majority of rUTIs are clinically categorized as reinfections [7]. On the other hand, women are vulnerable to UTIs because of their anatomical structure [8], including the fact that women have (1) a short distance between the urethral meatus and non-sterile anus, which allows for easier access for uropathogens to the lower urinary tract, and (2) a short urethral length without a complex structure, which facilitates the entry of uropathogens into the bladder. In addition, susceptibility to rUTIs may increase with frequent sexual intercourse and the use of spermicide in young women, in addition to increased prevalence in post-menopausal women due to their deficiency of estrogen, resulting in uropathogenic colonization [9].
Overall, the investigation of alternative strategies to decrease the occurrence of rUTIs is of interest to physicians and scientists. We believe that a better understanding of the pathogenicity of uropathogens, particularly for uropathogenic Escherichia coli (UPEC), can lead to the development of antivirulence treatment strategies other than antibiotics. Here, we review the components of the pathogenicity of uncomplicated rUTIs and virulence factors of UPEC and discuss potential approaches for targeting of the pathogenicity to limit rUTIs.

2. How Do Microorganisms Become Uropathogens?

Commensal microorganisms normally reside in the lower gastrointestinal tract of humans as a part of their microbiota. Few non-pathogenic organisms may acquire specific virulence through successful horizontal gene transfer, further causing UTIs [10,11]. Among these, UPEC is the main uropathogenic organism [12]. Other bacteria that cause uncomplicated UTIs include Proteus mirabilis, Klebsiella pneumonia, and other Enterobacteriaceae.

2.1. Uropathogenic Escherichia coli (UPEC)

E. coli strains that cause UTIs are termed UPEC. UPEC, which belongs to the group of extraintestinal E. coli, can be classified into eight serogroups (O1, O2, O4, O6, O7, O16, O18, and O75) based on its distinct surface O antigens, which represent the different functions of the variable repeating terminal polysaccharides attached to lipopolysaccharide [13], and is principally classified into two phylogenetic groups (B2 and D) based on a phylogenetic analysis using multilocus enzyme electrophoresis [14,15] (Table 1).

2.2. The Virulence Factors of UPEC

UPEC is different from harmless commensal fecal E. coli owing to the expression of particular virulence factors that specifically enhance their ability to colonize the urinary tract and cause UTIs [21]. Several key virulence factors include: (1) variable adhesins, as the crucial step for the irreversible attachment and adherence to uroepithelial cells over the lower urinary tract [22]; (2) the three main toxins secreted by UPEC: α-hemolysin, cytotoxic necrotizing factor 1 (CNF-1), and autotransporters, among which α-hemolysin is the most vital virulence factor associated with pyelonephritis. These toxins enhance exfoliation of the bladder epithelial cells, cause apoptosis of the host cells, cross mucosal carriers, and enable access to nutrients and iron stores of the host [23]; (3) autotransporters, consisting of secreted autotransporter toxin (SAT) and vacuolating autotransporter toxin (VAT), which induce cellular damage in renal and bladder cells, vacuole formation, cell elongation, autophagy induction, degradation of coagulation factor V, and dysregulation of the epithelial barrier of the bladder [24,25,26]; (4) systems for iron acquisition, namely siderophores, which ensure adequate levels of intracellular iron to maintain the survival of bacteria within the host urinary tract [22]; and (5) flagella, which mediate motility to enhance the ascending nature of UPEC [22]. Table 2 summarizes the various adhesive fimbriae, toxins, and autotransporters that contribute to virulence in UPEC.

3. Acute Uncomplicated Cystitis

Acute uncomplicated cystitis (AUC) occurs when uropathogens from the bowel or vagina colonize the periurethral mucosa and reach the bladder, causing a symptomatic UTI. Infections of the urinary tract depend on the combination of virulent invasion of uropathogens, inadequate host defenses by the immune response, and other predisposing factors.

3.1. The Adaptive Evolution of UPEC in UTI to Thrive within Urothelial Cells

The adaptive evolution of uropathogen infection includes two mechanisms: invasion of uroepithelial cells and persistence to survive intracellularly (Figure 1).
After the colonization of uropathogens, the preliminary step of UTI relies on adhesins, especially type I fimbriae, which enable uropathogens to recognize specific extracellular matrix proteins (laminin, fibronectin, collagen, and Tamm–Horsfall proteins) on the bladder epithelium, thereby binding to uroepithelial cells [27,28]. Furthermore, P fimbriae related to the process of invasion mediate other mannose-resistant adhesins. At this moment, some uropathogens are initially cleared by the first wave of host inflammatory responses, while others avoid the host’s defenses by intracellular invasion or morphological changes that are resistant to neutrophils. After intracellular invasion, they reside within vesicles by forming biofilms and undergo rapid and massive replication to establish intracellular bacterial communities within the cytosol of urothelial cells [22,41,42]. In addition, biofilms, which manifest as the presence of an extracellular matrix capable of containing proteins; polysaccharides; and DNA increase both the persistence and antibiotic resistance of intracellular UPEC.
However, the intracellular environment is inadequate for the survival of UPEC. Therefore, several strategies were developed for the intracellular survival of UPEC, which are summarized in Table 3, including (1) aerobic respiration to establish UTI by intracellular oxygen scavenging from the cytosol through cytochrome bd [43], the aim of which is to antagonize host apoptosis, thereby protecting intracellular uropathogens from the host cells’ exfoliation and supporting their replicative environment; (2) iron acquisition for cellular processes and bacterial growth by siderophores and/or other iron acquisition systems; the siderophores, known as yersiniabactin, salmochelin, enterobactin, and aerobactin, are capable of scavenging iron from the environment and further concentrating it in the bacterial cytosol. Different stains of UPEC have evolved iron acquisition systems to swipe iron from the host; furthermore, significantly higher levels of yersiniabactin and salmochelin were reported in UPEC than that in E.coli from the rectum, indicating their specific role in pathogenesis within the urinary tract [44]; (3) zinc acquisition by zinc-transport systems for iron hemostasis and relief of oxidative stress to maintain cellular function [45]; and (4) toxin secretion, which results in cytotoxic activity and destruction of the immune cells, further gaining access to nutrients from the hosts [14].

3.2. Host Defenses by Immune Response

Upon causing acute cystitis, UPEC induces several responses in the host against uropathogens in the bladder, including (1) inflammation by secreting cytokines, such as IL-1β, IL-6, and IL-8, to kill bacteria and to recruit the hosts’ inflammatory cells, namely neutrophils, monocytes, and mast cells, from the body to the uroepithelium [47]. The activation of Toll-like receptor 4 by the lipopolysaccharide, which is released by UPEC, increases the intracellular cAMP and causes the exocytosis of fusiform vesicles containing uropathogens [48,49]; (2) classical extrinsic and intrinsic apoptotic cascades of uroepithelial cells activated by FimH following the binding between type I fimbriae and uroplakins [50]. The exfoliation of superficial uroepithelial cells helps to eliminate intracellular uropathogens; furthermore, cell autophagy is critical in treatment to mediate the persistence of uropathogens in the bladder [51]; (3) antimicrobial defenses by upregulated antimicrobial peptides and proteins such as pentraxin 3, ribonuclease 7, cathelicidin, and defensins secreted by the urothelium and resident immune cells [52]; (4) deprivation of nutrients, such as by decreasing the amount of iron available to the pathogens, by the host’s innate immune system activated during UTI to limit the growth of uropathogens [53,54]. The host’s neutrophils produce lipocalin-2, which is capable of binding to the enterobactin siderophore against enterobactin-mediated iron uptake by UPEC. Notably, other UPEC evolved to utilize salmochelin siderophores, which cannot be recognized by neutrophils that produce lipocalin-2 [55]. In addition, the host’s neutrophil-derived protein, calprotein, is responsible for the sequestration of zinc and manganese and restriction of the growth of uropathogens [53]. The pathogenesis and defenses of the host with regard to acute cystitis and potential treatment strategies are summarized in Table 4.
Recently, emerging evidence has suggested that some biomarkers related to host immune responses may play important roles in predicting rUTIs in patients with a first UTI [56]. Potential biomarkers included urinary IL-8, urinary neutrophil gelatinase-associated lipocalin, serum vitamin D, and serum colony stimulating factors [56]. However, further large, prospective studies are necessary to verify those biomarkers as predictors of rUTI and identify their tole in the prevention and treatment of rUTIs.

3.3. Urinary Microbiome in Acute Cystitis

The discovery of microbial communities in the lower urinary tract using recent advanced technologies, such as culture-independent DNA sequencing, has changed the perception that urine is sterile. More than 100 species from more than 50 genera were observed in the human urogenital tract [57]. Subsequently, studies have suggested that the imbalance of the resident urinary microbial community may potentially be associated with UTIs [58]. The presence of different bacterial species in the male and female urinary microbiomes suggests that gender-specific factors may play a role in the colonization and maintenance of these microbial communities [59,60]. Shigella, Lactobacillus, Enterococcus, Gardnerella, Prevotella, Sneathia, Escherichia, and Streptococcus are observed to be prevalent in the female urobiome [61,62], while Corynebacterium has been identified as the dominant genus in the male urobiome [59]. The characteristics of the predominant urobiome are summarized in Table 5.
Lactobacillus, the dominant genus in the healthy female urinary and vaginal microbiome, enables the maintenance of a lower pH level due to the presence of lactic acid and hydrogen peroxide and inhibits the growth of uropathogens, degrades mycotoxins, and becomes a probiotic [63,64,65,66,67]. An imbalance from the healthy microbiome, for example, decreased levels of Lactobacillus, has been reported to be associated with rUTIs and urinary incontinence [68,69]. Gardnerella has been reported as a factor that has the potential to cause the re-emergence of UPEC from latent intracellular reservoirs and is associated with severe kidney infections and epithelial exfoliation [70,71] Therefore, an overgrowth of Gardnerella is associated with an increased risk of UTI and pyelonephritis in women [72,73]. Notably, increases in Gardnerella species also lead to decreases in Lactobacillus species [74]. However, whether dysbiosis between bacterial species actually results in disease remains to be elucidated.
Table
Table 5. Common urinary microbiome found in healthy women and men.
Table 5. Common urinary microbiome found in healthy women and men.
UrobiomePredominantly Found inClinical SignificanceReference
ShigellaWomen
  • It is commonly found in the urobiomes of both healthy men and women.
  • Shigella species rarely causes UTI; however, if they does, they can be responsible for UTI during pregnancy:
 [75]
LactobacillusWomen
  • Inhibiting the attachment of uropathogens to uroepithelial cells;
  • Antimicrobial activity against the uropathogens by inhibiting the growth of uropathogens;
  • Protective and anti-inflamatory roles;
  • A potential candidate as a probiotic for the prevention and treatment of UTIs.
 [76,77,78,79]
GardnerellaWomen
  • An increase in the vaginal microbiome post sexual intercourse → bacterial vaginosis.
  • Gardnerella enables triggering of UPEC-related rUTIs, causing bladder epithelial exfoliation, inducing apoptosis in the bladder epithelium, and causing kidney inflammation.
  • An increase in Gardnerella results in a decrease in the level of Lactobacillus species in urine.
 [70,80]
PrevotellaWomen
  • It is commonly found in the urobiomes of both healthy men and women.
 [58]
StreptococcusWomen
  • An increase in Streptococcus is linked to sexual intercourse.
 [81]
CorynebacteriumMen
  • Corynebacterium species are parts of the normal microflora;
  • Occurs in 0.2% of vaginal microflora samples of healthy women;
  • Occurs in the semen of men with prostatitis;
  • Found in the urine of patients with an overactive bladder and urinary incontinence.
 [82,83]

4. MDR Uropathogens

Antibiotics, especially repetitive antibiotic therapy (“collateral damage”), are the main cause for the development of antibiotic resistance, and such prolonged treatments can lead to increased resistance [84,85]. Unfortunately, almost half of patients with uncomplicated UTIs receive inappropriate or suboptimal prescriptions of antibiotics, which fail to eliminate uropathogens and can lead to a higher prevalence of MDR uropathogens, an increase in recurrent UTIs, and higher healthcare costs [86,87]. In recent decades, the incidence of highly resistant Escherichia coli and other enteric bacteria has been on the rise, making up an estimated 25–54% of all uropathogens [88].
The vast majority of UPEC shows intracellular invasion within 48 h after infection and forms biofilms, which protect from environmental challenges, including antibiotics and the host immune response [89]. Uropathogens respond to antibiotic treatment by regulating stress response mechanisms, including mutation and modification of the genome, production of enzymes to defend against antibiotics, and regulation of membrane permeability to resist antibiotic stress [90,91,92]. In antibiotic stress responses, uropathogens utilize horizontal gene transfer, which is the movement of genetic information between organisms and a process for the spread of antibiotic resistance genes among bacteria to fuel uropathogen evolution. The overexpression of marA in uropathogens is a concerning finding, as it can contribute to the development of multidrug resistance and increase the difficulty of treating UTIs [93]. MarA has been shown to activate several important virulence factors in UPEC, which can enhance the ability of the pathogen to colonize and infect the urinary tract [93]. Additionally, marA is involved in the regulation of the multidrug efflux system, which can help uropathogens to resist the effects of antibiotics [94,95,96]. Other genes have also been identified as playing a role in the antibiotic resistance of uropathogens, including rapA-regulated genes, yafQ, ymgB, and yhcQ [97,98,99]. Further research is needed to fully understand the mechanisms by which these genes contribute to antibiotic resistance in uropathogens and to develop new strategies for the prevention and treatment of antibiotic-resistant UTIs.

5. Emerging Prevention and Treatment Options Targeting UPEC

Because of the increasing antibiotic resistance of uropathogens, alterations in the physiological gut microbiota during treatment, and challenges in the prevention of rUTIs, different therapeutic and preventive strategies have been developed to target the pathogenicity of uropathogens. In addition to antibiotics for the treatment of symptomatic acute cystitis and low-dose antibiotic prophylaxis for rUTIs [84], alternative treatment options can be considered as a preventive strategy for UTIs (as summarized in Figure 2), although evidence of the efficacy of these options remains limited [85,100].

5.1. Decrease in the Periurethral Colonization of Uropathogens

Strategies to decrease periurethral colonization by uropathogens include behavioral modifications and vaginal hormonal replacement for rUTI prevention. Behavioral modifications include sufficient hydration with adequate urine output, avoidance of habitual and post-coital delayed urination, wiping from front to back after defecation, and the development of good hygiene habits [69].

5.1.1. Topical Estrogen Therapy and Vaginal Laser Therapy

Vaginal estrogen transition reduces the vaginal colonization of uropathogens and further limits rUTIs through the following means: (1) an increase in the Lactobacillus population, which restores the vaginal flora similar to that of a premenopausal state, with an accompanying acidifying vaginal pH level [101]; (2) induction of the expression of antimicrobial peptides, which enhances the antimicrobial capacity of the uroepithelium and restricts the replication of uropathogens [102]; and (3) an increase in the expression of intercellular junction proteins, which strengthens the attachment between uroepithelial cells, preventing uropathogens from coming into contact with deeper layers of the uroepithelium and limiting the formation of reservoirs for rUTIs [103].
Meta-analyses have shown that topical estrogen (either as creams, pessaries, or per-vaginal tablets)—not oral estrogen—is an effective prophylaxis for rUTIs in women [84,104,105,106], although vaginal estrogen is not approved by the US Food and Drug Administration for the prevention of UTIs. The administration of weekly topical doses ≥ 850 μg is associated with high efficacy [107]. However, 22–67% of women undergoing vaginal estrogen therapy were reported to have rUTIs [85,108]. Hence, additional combined strategies should be considered in future studies.
Recently, vaginal laser therapy has been used to restore vaginal mucosal thickness, lubrication, and elasticity, with good effect in menopausal women with a genitourinary syndrome of menopause (GSM), which results in vaginal dryness, pain, and UTI. The authors are aware of an ongoing study investigating fractional CO2 vaginal laser therapy against vaginal estrogen therapy for improvement in rUTI [109]; however, the data are not yet available.

5.1.2. Prophylaxis with Probiotics

Similar to the gastrointestinal tract, the urogenital tract contains a variety of microbes that are critical for the balance of the urinary microenvironment by altering local metabolite concentrations and pH levels [110]. Through next-generation sequencing and advanced culturing techniques, urinary microorganisms have been found to differ between healthy populations and those with UTIs [111], which points to the existence of a bladder microbiome [63,111]. Beneficial urinary Lactobacillus species, which produce lactic acid and decrease the vaginal pH, have been shown to decrease in patients with UTIs [112]. Therefore, probiotic supplementation could theoretically enhance protective microbe colonization, compete for nutrients, inhibit uropathogen biofilms, and potentially prevent UTIs [58]. Six meta-analyses and one meta-analysis targeting children were identified [84,113,114,115,116,117]; three meta-analyses reported significant positive effects of using probiotics for rUTI prevention compared to placebo in women and children [113,114,115], while the other three did not demonstrate a significant benefit in reducing UTI recurrence with probiotics compared to placebo in women [63,84,85,105,106,107,108,109,110,111,112,113,114,115,116,117]. Among the included studies, there was a lack of standardization of dose, strain, and frequency, which may impact the quantitative analysis of the outcomes, leading to contradictory results.
In addition, most studies have found that not all Lactobacillus species are effective, which may lead to inconsistent results. The highest efficacy was shown with L. rhamnosus GR-1, L. reuteri B-54, L. reuteri RC-14, L. casei shirota, and L. crispatus CTV-05 [84,113,114,117]. Therefore, probiotics containing these five strains were recommended by the 2022 EAU guidelines for the prevention of rUTI [118].

5.2. Antiadhesive Treatments

Antiadhesive treatments include cranberries, D-mannose, glycosaminoglycan (GAG)-layer substituents, and vaccines targeting bacterial adhesion.

5.2.1. Cranberries (Vaccinium macrocarpon)

Cranberries contain high concentrations of proanthocyanins (PACs) and oligo- or polymers of monomeric flavan-3-ols produced as an end product of the flavonoid biosynthetic pathway. These compounds have been found in several plants, such as cranberry, blueberry, and grape seeds [119]. The advantages of PACs against UTIs include (1) anti-adhesion against P fimbriae of UPEC adherence to uroepithelial cell receptors, which is activated when the concentration of PAC is 2.4 mg/mL [120]; (2) an inhibitory effect on the bacterial motility of UPEC, Pseudomonas aeruginosa, and Proteus mirabilis [121,122]; (3) anti-biofilm activity, which is effective when the concentration of PAC is 15 μg/mL (MBIC50) from cinnamon [123]; (4) attenuation of the uropathogen reservoir in the gastrointestinal tract; (5) stimulation of innate immune defense in the kidney by increasing the secretion of Tamm–Horsfall protein [124,125]; and (6) synergistic effects with antibiotics against bacteria through the repression of the intrinsic resistance mechanism and additional biofilm inhibition of the action of existing antibiotics [126,127].
A Cochrane review updated in 2012 reported that cranberries do not have significant benefits in terms of decreasing the number of UTIs, and a high dropout rate was found in the cranberry group [128]. However, recent meta-analyses and systematic reviews concluded that cranberry-containing products may protect against UTIs in certain patient populations [84,129,130,131,132], especially in women, children (2–17 years), and middle-aged adults (36–55 years) [129]. The daily recommended dosage of PACs to decrease episodes of UTIs is reported to be at least 36 mg [129]. The different outcomes across the meta-analyses can be attributed to the heterogeneity in clinical diagnosis (e.g., absence of confirmation of E. coli UTI) and methodology of the included studies [133]. Among the included studies, the study duration ranged from 35 days to 12 months; therefore, there is no evidence to support the efficacy of cranberries for chronic use, especially for more than one year. Due to the disagreement in scientific evidence, the 2022 EAU guidelines do not recommend cranberry products for the prevention of UTIs [118].

5.2.2. D-Mannose

D-mannose is a low-molecular-weight compound and a FimH receptor analogue recognized and bound by uropathogens. It is a food-derived product with medical benefits, as well as nutritional benefits, and is capable of blocking the adherence of bacteria to uroepithelial cells mediated by FimH adhesin, which functions as the tip subunit of type 1 pili [134,135,136,137]. Mannose is orally bioavailable, rapidly absorbed, and safely secreted in the urine.
The effects of mannose were proven in vivo, which included: (1) prevention of bladder uropathogen colonization and invasion, (2) effectiveness against multidrug-resistant UPEC, (3) enhancement of the effect of antibiotics, and (4) enabling the treatment of UTIs and catheter-associated UTIs [136,137,138,139].
One meta-analysis and two systematic reviews, including four randomized controlled trials and several studies, were identified [140,141,142,143,144], which concluded that D-mannose reduced rUTI significantly in subjects, both with and without catheter and prolonged UTI-free duration. However, similar to cranberries, the dose, regime, and duration lack consistency among different clinical studies [142,143]. The other limitations were small sample sizes (less than 100 patients), non-blinded studies, and self-reported rUTIs. Overall, the 2022 EAU guidelines recommend the use of D-mannose to reduce recurrent UTI episodes; however, patients should be informed that further studies are warranted to confirm the efficacy of D-mannose in initial trials [118].

5.2.3. GAG Layer Substituents

The glycosaminoglycan (GAG) layer, which is coated on the bladder epithelium, has a nonspecific antiadherence role and a nonspecific protective mechanism against UTIs. Re-establishment of the GAG layer can be achieved by two main types of GAG: non-sulfated GAG, namely hyaluronic acid (HA); and sulfated GAG, namely chondroitin sulfate (CS), heparan sulfate, heparin, dermatan sulfate, and keratan sulfate. GAG layer replenishment of the bladder epithelium, which has been effectively used in different chronic inflammatory bladder diseases, such as interstitial cystitis, overactive bladder, and radiation cystitis, is a promising strategy for the management of rUTIs [144]. Two randomized controlled trials conducted to evaluate the efficacy of HA plus CS in intravesical instillation for adult women confirmed the positive effect of reducing the frequency of rUTIs and increasing the interval before the first rUTI [145,146]. In the 2022 EAU guidelines, intravesical GAG therapy was weakly recommended in patients who failed to prevent rUTI using less invasive preventive approaches [118].

5.3. Alternative Antibacterial Management

5.3.1. Methenamine Hippurate

Methenamine hippurate, a urinary antiseptic and non-antibiotic alternative, is hydrolyzed to formaldehyde in acidic environments, such as the distal tubules in the kidney. Formaldehyde is bactericidal and functions by denaturing bacterial proteins and nucleic acids. Methenamine hippurate does not have the potential to cause the same antibiotic resistance as daily low-dose antibiotics in the prevention of rUTI and may be considered as a first-line therapy in the future.
A 2012 evidence-based Cochrane review concluded that methenamine hippurate has the benefit of preventing UTIs [147]. In contrast, another meta-analysis conducted in 2021 based on six RCTs comparing intervention to both control/no treatment and to any antibiotics and only considering women in the community suggested that no statistically significant outcome was found between methenamine hippurate and any comparators [148]. More recently, two RCTs, both comparing methenamine hippurate with the current standard care of daily low-dose antibiotics for 6–12 months, showed that methenamine hippurate is not inferior to low-dose antibiotics in preventing rUTI for 12 months after the initiation of prophylaxis [149,150]. Because of these controversial results, the 2022 EAU does not recommend the use of methenamine hippurate [118].

5.3.2. Immunomodulation Therapy

Hyperactivation of IL-1β triggered by UPEC infection of the uroepithelium has been prominently identified in the pathogenicity of acute cystitis [47]. Indeed, IL-1β, a potential proinflammatory cytokine, amplifies the innate immune response in chronic infection/inflammatory models, such as tuberculosis, cystic fibrosis, and inflammatory bowel disease [151,152,153,154]. IL-1β and its receptor may be potential treatment targets for acute cystitis; therefore, the recombinant human IL-1 receptor antagonist (IL-1RA), which is an inhibitor of IL-1β hyperactivation, was developed.
To demonstrate the anti-inflammatory effects of IL-1RA in several diseases, including cystic fibrosis and COVID-19 [155,156,157], IL-1RA was studied in mice infected with UPEC [156], in which IL-1RA therapy accelerated bacterial clearance. Additionally, a similar effect was shown to be comparable to cefotaxime treatment. Based on the promising results of innate immunomodulation therapy in a mouse model of acute cystitis, further clinical trials of IL-1RA therapy for acute cystitis are required in the future.

5.3.3. Vaccine Prophylaxis

Antibacterial vaccination strategies have been recently implemented to boost adaptive immunity due to their ability to prevent infection by highly virulent organisms.

Vaccines Targeting Bacterial Adhesion

Vaccines targeting bacterial adhesion have been developed in two domains: (1) bacterial adherence, which is related to pili or fimbriae, for example, a vaccine with purified wild-type Dr fimbriae can induce a humoral immunogenic response and further produce antibiotics against UTI but could cannot decrease the colonization in the bladder and kidney [158,159]; (2) adhesive proteins, namely adhesion–chaperone complexes, are effective in blocking the interactions between uropathogens and hosts and further protect the host against UTIs [160,161,162]. Gary et al. [163] conducted a phase I, open-label, dose escalation study to evaluate the efficacy of a FimC-FimH vaccine in 67 healthy women with and without histories of rUTI, and the results showed that all subjects tolerated the vaccine well, with greater than 150-fold increases in antibodies against the N-terminal region of FimH in the women with histories of rUTI; a further double-blind, randomized, placebocontrolled phase 2 study is currently being conducted.

Vaccines Containing Bacterial Extracts

Uro-Vaxom (OM-89), which contains lyophilized UPEC lysates, is administered as a daily oral tablet to prevent rUTIs by stimulating the host immune system to produce cytokines and antibodies [84,164,165,166]. The EAU guidelines recommend the prophylactic use of OM-89 because several meta-analyses have demonstrated its effectiveness in preventing rUTIs compared to a placebo at the 6-month follow-up [84,164,165,166], in which OM-89 resulted in a 39% reduction in UTIs, with minimal adverse effects compared to the placebo. Therefore, the 2022 EAU guidelines strongly recommend the use of OM-89 in female patients with rUTIs [118].

Vaccines Targeting Bacterial Toxins and Proteases

Vaccines targeting bacterial toxins have been developed, including vaccines with (1) toxin HlyA, which reduced renal scarring but did not protect against the colonization of UPEC in the kidneys [167]; (2) HpmA, the pore-forming secreted hemolysin of P. mirabilis, which did not reduce bacterial colonization [168]; and (3) proteus toxic agglutinin (Pta), a surface-associated, calcium-dependent alkaline protease that exhibits time- and dose-dependent cytotoxicity with cultured epithelial cells, which reduces kidney bacterial colonization, although it does not provide protection against bladder colonization [168].

Vaccines Targeting Siderophores

Vaccines targeting bacterial nutrient deprivation have been developed based on different iron acquisition systems of uropathogens, including (1) ferric yersiniabactin uptake receptor (FyuA), which showed protective effects against pyelonephritis in a murine model [169]; (2) heme acquisition protein (Hma), which provided significant protection from UPEC strain 536 bladder colonization [170]; (3) iron suptake transport aerobactin receptor (IutA), which protected the bladder from experimental challenge with UPEC by generating significant induction of antigen-specific IgA secretion that is detectable in the urine of immunized animals [170]; and (4) siderophore receptor iron-responsive element A (IreA), which reduced colonization by UPEC strain 536 in the kidney [170].

6. Conclusions

This review highlights the importance of the pathogenicity of uropathogens causing acute cystitis, the level of evidence for currently available treatments, and potential treatment and preventive strategies derived from pathogenic mechanisms. Various strategies for UTI management and rUTI prevention other than antibiotics present both challenges and opportunities. The targeting of multiple pathogenic mechanisms is expected to be a future trend in the management of UTIs to reduce the occurrence of rUTIs, reduce the use of antibiotics, and further decrease antibiotic resistance.

Author Contributions

Conceptualization, Y.-C.C. (Yu-Chen Chen) and W.-C.L.; writing—original draft preparation, Y.-C.C. (Yu-Chen Chen); writing—review and editing, W.-C.L. and Y.-C.C. (Yao-Chi Chuang); supervision, W.-C.L. and Y.-C.C. (Yao-Chi Chuang); project administration, Y.-C.C. (Yu-Chen Chen) and W.-C.L.; funding acquisition, Y.-C.C. (Yu-Chen Chen) and W.-C.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by grants MOST 111-2314-B-182A-081-MY3 from the Ministry of Science and Technology of the Republic of China and CMRPG8M0741 and CORPG8M0171 from the Chang Gung Medical Foundation and Chang Gung Memorial Hospital, as well as by Kaohsiung Medical University Hospital (grant numbers KMUH-110-0M57 and KMUH111-1M48).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors appreciate the generous grants from the Kaohsiung Medical University Hospital, Ministry of Science and Technology of the Republic of China, the Chang Gung Medical Foundation and Chang Gung Memorial Hospital.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Wagenlehner, F.M.E.; Bjerklund Johansen, T.E.; Cai, T.; Koves, B.; Kranz, J.; Pilatz, A.; Tandogdu, Z. Epidemiology, definition and treatment of complicated urinary tract infections. Nat. Rev. Urol. 2020, 17, 586–600. [Google Scholar] [CrossRef] [PubMed]
  2. Smith, A.L.; Brown, J.; Wyman, J.F.; Berry, A.; Newman, D.K.; Stapleton, A.E. Treatment and Prevention of Recurrent Lower Urinary Tract Infections in Women: A Rapid Review with Practice Recommendations. J. Urol. 2018, 200, 1174–1191. [Google Scholar] [CrossRef]
  3. Goebel, M.C.; Trautner, B.W.; Grigoryan, L. The Five Ds of Outpatient Antibiotic Stewardship for Urinary Tract Infections. Clin. Microbiol. Rev. 2021, 34, e0000320. [Google Scholar] [CrossRef] [PubMed]
  4. Larsson, S.; Edlund, C.; Nauclér, P.; Svensson, M.; Ternhag, A. Cost-Effectiveness Analysis of Temocillin Treatment in Patients with Febrile UTI Accounting for the Emergence of Antibiotic Resistance. Appl. Health Econ. Health Policy 2022, 20, 835–843. [Google Scholar] [CrossRef] [PubMed]
  5. World Health Organization. Antibiotic Resistance; WHO: Geneva, Switzerland, 2018.
  6. Kang, C.; Kim, J.; Park, D.W.; Kim, B.N.; Ha, U.S.; Lee, S.J.; Yeo, J.K.; Min, S.K.; Lee, H.; Wie, S.H. Clinical Practice Guidelines for the Antibiotic Treatment of Community-Acquired Urinary Tract Infections. Infect. Chemother. 2018, 50, 67–100. [Google Scholar] [CrossRef]
  7. Zare, M.; Vehreschild, M.J.G.T.; Wagenlehner, F. Management of uncomplicated recurrent urinary tract infections. BJU Int. 2022, 129, 668–678. [Google Scholar] [CrossRef]
  8. Cai, T. Recurrent uncomplicated urinary tract infections: Definitions and risk factors. GMS Infect Dis. 2021, 27, 9. [Google Scholar]
  9. Jung, C.; Brubaker, L. The etiology and management of recurrent urinary tract infections in postmenopausal women. Climacteric 2019, 22, 242–249. [Google Scholar] [CrossRef]
  10. Javadi, M.; Bouzari, S.; Oloomi, M. Horizontal Gene Transfer and the Diversity of Escherichia coli. In Escherichia coli—Recent Advances on Physiology, Pathogenesis and Biotechnological Applications; Samie, A., Ed.; IntechOpen: London, UK, 2017. [Google Scholar] [CrossRef] [Green Version]
  11. Ogura, Y.; Ooka, T.; Iguchi, A.; Toh, H.; Asadulghani, M.; Oshima, K.; Kodama, T.; Abe, H.; Nakayama, K.; Kurokawa, K.; et al. Comparative genomics reveal the mechanism of the parallel evolution of O157 and non-O157 enterohemorrhagic Escherichia coli. Proc. Natl. Acad. Sci. USA 2009, 106, 17939–17944. [Google Scholar] [CrossRef] [Green Version]
  12. Gupta, K.; Hooton, T.M.; Naber, K.G.; Wullt, B.; Colgan, R.; Miller, L.G.; Moran, G.J.; Nicolle, L.E.; Raz, R.; Schaeffer, A.J.; et al. Infectious Diseases Society of America; European Society for Microbiology and Infectious Diseases. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin. Infect. Dis. 2011, 52, e103–e120. [Google Scholar]
  13. Aubron, C.; Glodt, J.; Matar, C.; Huet, O.; Borderie, D.; Dobrindt, U.; Duranteau, J.; Denamur, E.; Conti, M.; Bouvet, O. Variation in endogenous oxidative stress in Escherichia coli natural isolates during growth in urine. BMC Microbiol. 2012, 12, 120. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Kaur, N.; Agarwal, A.; Grover, M.; Singh, S. Uropathogenic Escherichia coli. In Enterobacteria; IntechOpen: London, UK, 2022. [Google Scholar] [CrossRef]
  15. Hochhut, B.; Wilde, C.; Balling, G.; Middendorf, B.; Dobrindt, U.; Brzuszkiewicz, E.; Gottschalk, G.; Carniel, E.; Hacker, J. Role of pathogenicity island-associated integrases in the genome plasticity of uropathogenic Escherichia coli strain 536. Mol. Microbiol. 2006, 61, 584–595. [Google Scholar] [CrossRef] [PubMed]
  16. Brzuszkiewicz, E.; Brüggemann, H.; Liesegang, H.; Emmerth, M.; Olschläger, T.; Nagy, G.; Albermann, K.; Wagner, C.; Buchrieser, C.; Emody, L.; et al. How to become a uropathogen: Comparative genomic analysis of extraintestinal pathogenic Escherichia coli strains. Proc. Natl. Acad. Sci. USA 2006, 103, 12879–12884. [Google Scholar] [CrossRef] [Green Version]
  17. Luo, C.; Hu, G.Q.; Zhu, H. Genome reannotation of Escherichia coli CFT073 with new insights into virulence. BMC Genom. 2009, 10, 552. [Google Scholar] [CrossRef] [Green Version]
  18. Ulett, G.C.; Mabbett, A.N.; Fung, K.C.; Webb, R.I.; Schembri, M.A. The role of F9 fimbriae of uropathogenic Escherichia coli in biofilm formation. Microbiology 2007, 153, 2321–2331. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. Hadjifrangiskou, M.; Gu, A.P.; Pinkner, J.S.; Kostakioti, M.; Zhang, E.W.; Greene, S.E.; Hultgren, S.J. Transposon mutagenesis identifies uropathogenic Escherichia coli biofilm factors. J. Bacterial. 2012, 194, 6195–6205. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Koch, D.; Chan, A.C.; Murphy, M.E.; Lilie, H.; Grass, G.; Nies, D.H. Characterization of a dipartite iron uptake system from uropathogenic Escherichia coli strain F11. J. Biol. Chem. 2011, 286, 25317–25330. [Google Scholar] [CrossRef] [Green Version]
  21. Nicolosi, D.; Tempera, G.; Genovese, C.; Furneri, P.M. Anti-Adhesion Activity of A2-type Proanthocyanidins (a Cranberry Major Component) on Uropathogenic, E. coli and P. mirabilis Strains. Antibiotics 2014, 3, 143–154. [Google Scholar] [CrossRef]
  22. Klein, R.D.; Hultgren, S.J. Urinary tract infections: Microbial pathogenesis, host-pathogen interactions and new treatment strategies. Nat. Rev. Microbiol. 2020, 18, 211–226. [Google Scholar] [CrossRef]
  23. Chen, M.; Tofighi, R.; Bao, W.; Aspevall, O.; Jahnukainen, T.; Gustafsson, L.E.; Ceccatelli, S.; Celsi, G. Carbon monoxide prevents apoptosis induced by uropathogenic Escherichia coli toxins. Pediatr. Nephrol. 2006, 21, 382–389. [Google Scholar] [CrossRef] [PubMed]
  24. Díaz, J.M.; Dozois, C.M.; Avelar-González, F.J.; Hernández-Cuellar, E.; Pokharel, P.; de Santiago, A.S.; Guerrero-Barrera, A.L. The Vacuolating Autotransporter Toxin (Vat) of Escherichia coli Causes Cell Cytoskeleton Changes and Produces Non-lysosomal Vacuole Formation in Bladder Epithelial Cells. Front. Cell. Infect. Microbiol. 2020, 10, 299. [Google Scholar] [CrossRef]
  25. Lie’vin-Le Moal, V.; Comenge, Y.; Ruby, V.; Amsellem, R.; Nicolas, V.; Servin, A.L. Secreted autotransporter toxin (Sat) triggers autophagy in epithelial cells that relies on cell detachment. Cell. Microbiol. 2011, 13, 992–1013. [Google Scholar] [CrossRef] [PubMed]
  26. Dutta, P.R.; Cappello, R.; Navarro-García, F.; Nataro, J.P. Functional comparison of serine protease autotransporters of enterobacteriaceae. Infect. Immun. 2002, 70, 7105–7113. [Google Scholar] [CrossRef] [Green Version]
  27. Marrs, C.F.; Zhang, L.; Foxman, B. Escherichia coli mediated urinary tract infections: Are there distinct uropathogenic E. coli (UPEC) pathotypes? FEMS Microbiol. Lett. 2005, 252, 183–190. [Google Scholar] [CrossRef] [Green Version]
  28. Das, M.; Tassell, A.H.-V.; Urvil, P.T.; Lea, S.; Pettigrew, D.; Anderson, K.L.; Samet, A.; Kur, J.; Matthews, S.; Nowicki, S.; et al. Hydrophilic domain II of Escherichia coli Dr fimbriae facilitates cell invasion. Infect. Immun. 2005, 73, 6119–6126. [Google Scholar] [CrossRef] [Green Version]
  29. Pizarro-Cerdá, J.; Cossart, P. Bacterial adhesion and entry into host cells. Cell 2006, 124, 715–727. [Google Scholar] [CrossRef] [Green Version]
  30. Ambite, I.; Butler, D.S.C.; Stork, C.; Grönberg-Hernández, J.; Köves, B.; Zdziarski, J.; Pinkner, J.; Hultgren, S.J.; Dobrindt, U.; Wullt, B.; et al. Fimbriae reprogram host gene expression—Divergent effects of P and type 1 fimbriae. PLoS Pathog. 2019, 15, e1007671. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  31. Ott, M.; Hoschutzky, H.; Jann, K.; Van Die, I.; Hacker, J. Gene clusters for S fimbrial adhesin (sfa) and F1C (foc) of Escherichia coli: Comparative aspects of structure and function. J. Bacteriol. 1998, 170, 3983–3990. [Google Scholar] [CrossRef] [Green Version]
  32. Siitonen, A.; Martikainen, R.; Ikaheimo, R.; Palmgren, J.; Mkela, P.H. Virulence-associated characteristics of Escherichia coli in urinary tract infection: A statistical analysis with special attention to type 1C fimbriation. Microb. Pathog. 1993, 15, 65–75. [Google Scholar] [CrossRef] [PubMed]
  33. Ristow, L.C.; Welch, R.A. Hemolysin of uropathogenic Escherichia coli: A cloak or a dagger? Biochim. Biophys. Acta 2016, 1858, 538–545. [Google Scholar] [CrossRef]
  34. Carlini, F.; Maroccia, Z.; Fiorentini, C.; Travaglione, S.; Fabbri, A. Effects of the Escherichia coli Bacterial Toxin Cytotoxic Necrotizing Factor 1 on Different Human and Animal Cells: A Systematic Review. Int. J. Mol. Sci. 2021, 22, 12610. [Google Scholar] [CrossRef] [PubMed]
  35. Piteau, M.; Papatheodorou, P.; Schwan, C.; Schlosser, A.; Aktories, K.; Schmidt, G. Lu/BCAM adhesion glycoprotein is a receptor for Escherichia coli Cytotoxic Necrotizing Factor 1 (CNF1). PLoS Pathog. 2014, 10, e1003884. [Google Scholar] [CrossRef]
  36. Reppin, F.; Cochet, S.; El Nemer, W.; Fritz, G.; Schmidt, G. High Affinity Binding of Escherichia coli Cytotoxic Necrotizing Factor 1 (CNF1) to Lu/BCAM Adhesion Glycoprotein. Toxins 2017, 10, 3. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Welch, R.A. Uropathogenic Escherichia coli-Associated Exotoxins. Microbiol. Spectr. 2016, 4, 10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Spurbeck, P.R.; Dinh, P.C., Jr.; Walk, S.T.; Stapleton, A.E.; Hooton, T.M.; Nolan, L.K.; Kim, K.S.; Johnson, J.R.; Mobley, H.L.T. Escherichia coli isolates that carry vat, fyuA, chuA, and yfcV efficiently colonize the urinary tract. Infect. Immun. 2012, 80, 4115–4122. [Google Scholar] [CrossRef] [Green Version]
  39. Nichols, K.B.; Totsika, M.; Moriel, D.G.; Lo, A.W.; Yang, J.; Wurpel, D.J.; Rossiter, A.E.; Strugnell, R.A.; Henderson, I.R.; Ulett, G.C.; et al. Molecular characterization of the vacuolating autotransporter toxin in uropathogenic Escherichia coli. J. Bacteriol. 2016, 198, 1487–1498. [Google Scholar] [CrossRef] [Green Version]
  40. Nava-Acosta, R.; Navarro-Garcia, F. Cytokeratin 8 is an epithelial cell receptor for pet, a cytotoxic serine protease autotransporter of Enterobacteriaceae. mBio 2013, 4, e00838-13. [Google Scholar] [CrossRef] [Green Version]
  41. Flores-Mireles, A.L.; Walker, J.N.; Caparon, M.; Hultgren, S.J. Urinary tract infections: Epidemiology, mechanisms of infection and treatment options. Nat. Rev. Microbiol. 2015, 13, 269–284. [Google Scholar] [CrossRef]
  42. Anderson, G.G.; Palermo, J.J.; Schilling, J.D.; Roth, R.; Heuser, J.; Hultgren, S.J. Intracellular bacterial biofilm-like pods in urinary tract infections. Science 2003, 301, 105–107. [Google Scholar] [CrossRef] [Green Version]
  43. Beebout, C.J.; Robertson, G.L.; Reinfeld, B.I.; Blee, A.M.; Morales, G.H.; Brannon, J.R.; Chazin, W.J.; Rathmell, W.K.; Rathmell, J.C.; Gama, V.; et al. Uropathogenic Escherichia coli subverts mitochondrial metabolism to enable intracellular bacterial pathogenesis in urinary tract infection. Nat. Microbiol. 2022, 7, 1348–1360. [Google Scholar] [CrossRef]
  44. Henderson, J.P.; Crowley, J.R.; Pinkner, J.S.; Walker, J.N.; Tsukayama, P.; Stamm, W.E.; Hooton, T.M.; Hultgren, S.J. Quantitative metabolomics reveals an epigenetic blueprint for iron acquisition in uropathogenic Escherichia coli. PLoS Pathog. 2009, 5, e1000305. [Google Scholar] [CrossRef]
  45. Sabri, M.; Houle, S.; Dozois, C.M. Roles of the extraintestinal pathogenic Escherichia coli ZnuACB and ZupT zinc transporters during urinary tract infection. Infect. Immun. 2009, 77, 1155–1164. [Google Scholar] [CrossRef] [Green Version]
  46. Ji, C.; Juárez-Hernández, R.E.; Miller, M.J. Exploiting bacterial iron acquisition: Siderophore conjugates. Future Med. Chem. 2012, 4, 297–313. [Google Scholar] [CrossRef]
  47. Ambite, I.; Puthia, M.; Nagy, K.; Cafaro, C.; Nadeem, A.; Butler, D.S.C.; Rydström, G.; Filenko, N.A.; Wullt, B.; Miethke, T.; et al. Molecular basis of acute cystitis reveals susceptibility genes and immunotherapeutic targets. PLoS Pathog. 2016, 12, e1005848. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. Song, J.; Duncan, M.J.; Li, G.; Chan, C.; Grady, R.; Stapleton, A.; Abraham, S.N. A novel TLR4-mediated signaling pathway leading to IL-6 responses in human bladder epithelial cells. PLoS Pathog. 2007, 3, e60. [Google Scholar] [CrossRef] [Green Version]
  49. Song, J.; Bishop, B.L.; Li, G.; Grady, R.; Stapleton, A.; Abraham, S.N. TLR4-mediated expulsion of bacteria from infected bladder epithelial cells. Proc. Natl. Acad. Sci. USA 2009, 106, 14966–14971. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  50. Klumpp, D.J.; Rycyk, M.T.; Chen, M.C.; Thumbikat, P.; Sengupta, S.; Schaeffer, A.J. Uropathogenic Escherichia coli induces extrinsic and intrinsic cascades to initiate urothelial apoptosis. Infect. Immun. 2006, 74, 5106–5113. [Google Scholar] [CrossRef] [Green Version]
  51. Wang, C.; Bauckman, K.A.; Ross, A.S.B.; Symington, J.W.; Ligon, M.M.; Scholtes, G.; Kumar, A.; Chang, H.-W.; Twentyman, J.; Fashemi, B.E.; et al. A non-canonical autophagy-dependent role of the ATG16L1(T300A) variant in urothelial vesicular trafficking and uropathogenic Escherichia coli persistence. Autophagy 2019, 15, 527–542. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Zasloff, M. The antibacterial shield of the human urinary tract. Kidney Int. 2013, 83, 548–550. [Google Scholar] [CrossRef] [Green Version]
  53. Corbin, B.D.; Seeley, E.H.; Raab, A.; Feldmann, J.; Miller, M.R.; Torres, V.J.; Anderson, K.L.; Dattilo, B.M.; Dunman, P.M.; Gerads, R.; et al. Metal chelation and inhibition of bacterial growth in tissue abscesses. Science 2008, 319, 962–965. [Google Scholar] [CrossRef] [PubMed]
  54. Haley, K.P.; Skaar, E.P. A battle for iron: Host sequestration and Staphylococcus aureus acquisition. Microbes Infect. 2012, 14, 217–227. [Google Scholar] [CrossRef] [Green Version]
  55. Flo, T.H.; Smith, K.D.; Sato, S.; Rodriguez, D.J.; Holmes, M.A.; Strong, R.K.; Akira, S.; Aderem, A. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 2004, 432, 917–921. [Google Scholar] [CrossRef]
  56. Sorić Hosman, I.; Cvitković Roić, A.; Lamot, L. A Systematic Review of the (Un)known Host Immune Response Biomarkers for Predicting Recurrence of Urinary Tract Infection. Front. Med. 2022, 9, 931717. [Google Scholar] [CrossRef]
  57. Neugent, M.L.; Hulyalkar, N.V.; Nguyen, V.H.; Zimmern, P.E.; De Nisco, N.J. Advances in Understanding the Human Urinary Microbiome and Its Potential Role in Urinary Tract Infection. mBio 2020, 11, e00218-20. [Google Scholar] [CrossRef]
  58. Kenneally, C.; Murphy, C.P.; Sleator, R.D.; Culligan, E.P. The urinary microbiome and biological therapeutics: Novel therapies for urinary tract infections. Microbiol. Res. 2022, 259, 127010. [Google Scholar] [CrossRef]
  59. Fouts, D.E.; Pieper, R.; Szpakowski, S.; Pohl, H.; Knoblach, S.; Suh, M.J.; Huang, S.T.; Ljungberg, I.; Sprague, B.M.; Lucas, S.K.; et al. Integrated next-generation sequencing of 16S rDNA and metaproteomics differentiate the healthy urine microbiome from asymptomatic bacteriuria in neuropathic bladder associated with spinal cord injury. J. Transl. Med. 2012, 10, 174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Ceprnja, M.; Oros, D.; Melvan, E.; Svetlicic, E.; Skrlin, J.; Barisic, K.; Starcevic, L.; Zucko, J.; Starcevic, A. Modeling of urinary microbiota associated with cystitis. Front. Cell. Infect. Microbiol. 2021, 11, 643638. [Google Scholar] [CrossRef] [PubMed]
  61. Gottschick, C.; Deng, Z.L.; Vital, M.; Masur, C.; Abels, C.; Pieper, D.H.; Wagner-Döbler, I. The urinary microbiota of men and women and its changes in women during bacterial vaginosis and antibiotic treatment. Microbiome 2017, 5, 99. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Price, T.K.; Hilt, E.E.; Thomas-White, K.; Mueller, E.R.; Wolfe, A.J.; Brubaker, L. The urobiome of continent adult women: A cross-sectional study. BJOG 2020, 127, 193–201. [Google Scholar] [CrossRef] [PubMed]
  63. Hilt, E.E.; McKinley, K.; Pearce, M.M.; Rosenfeld, A.B.; Zilliox, M.J.; Mueller, E.R.; Brubaker, L.; Gai, X.; Wolfe, A.J.; Schreckenberger, P.C. Urine is not sterile: Use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J. Clin. Microbiol. 2014, 52, 871–876. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Pearce, M.M.; Zilliox, M.J.; Rosenfeld, A.B.; Thomas-White, K.J.; Richter, H.E.; Nager, C.W.; Visco, A.G.; Nygaard, I.E.; Barber, M.D.; Schaffer, J.; et al. The female urinary microbiome in urgency urinary incontinence. Am. J. Obstet. Gynecol. 2015, 213, e1–e11. [Google Scholar] [CrossRef] [Green Version]
  65. Marrazzo, J.M. Interpreting the epidemiology and natural history of bacterial vaginosis: Are we still confused? Anaerobe 2011, 17, 186–190. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Cadieux, P.A.; Burton, J.P.; Devillard, E.; Reid, G. Lactobacillus by-products inhibit the growth and virulence of uropathogenic Escherichia coli. J. Physiol. Pharmacol. 2009, 60 (Suppl. 6), 13–18. [Google Scholar] [PubMed]
  67. Todorov, S.D. Bacteriocins from Lactobacillus plantarum—Production genetic organization. Braz. J. Microbiol. 2009, 40, 209–221. [Google Scholar] [CrossRef] [Green Version]
  68. Komesu, Y.M.; Richter, H.E.; Carper, B.; Dinwiddie, D.L.; Lukacz, E.S.; Siddiqui, N.Y.; Sung, V.W.; Zyczynski, H.M.; Ridgeway, B.; Rogers, R.G.; et al. The urinary microbiome in women with mixed urinary incontinence compared to similarly aged controls. Int. Urogynecol. J. 2018, 29, 1785–1795. [Google Scholar] [CrossRef]
  69. Stapleton, A.E. The vaginal microbiota and urinary tract infection. Microbiol. Spectr. 2016, 4, 10. [Google Scholar] [CrossRef] [Green Version]
  70. Gilbert, N.M.; O’Brien, V.P.; Lewis, A.L. Transient microbiota exposures activate dormant Escherichia coli infection in the bladder and drive severe outcomes of recurrent disease. PLoS Pathog. 2017, 13, e1006238. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  71. O’Brien, V.P.; Joens, M.S.; Lewis, A.L.; Gilbert, N.M. Recurrent Escherichia coli urinary tract infection triggered by gardnerella vaginalis bladder exposure in mice. J. Vis. Exp. 2020, 4, e61967. [Google Scholar] [CrossRef]
  72. Ravel, J.; Gajer, P.; Abdo, Z.; Schneider, G.M.; Koenig, S.S.K.; McCulle, S.L.; Karlebach, S.; Gorle, R.; Russell, J.; Tacket, C.O.; et al. Vaginal microbiome of reproductive-age women. Proc. Natl. Acad. Sci. USA 2011, 108 (Suppl. 1), 4680–4687. [Google Scholar] [CrossRef] [Green Version]
  73. Morrill, S.; Gilbert, N.M.; Lewis, A.L. Gardnerella vaginalis as a cause of bacterial vaginosis: Appraisal of the evidence from in vivo models. Front. Cell. Infect. Microbiol. 2020, 10, 168. [Google Scholar] [CrossRef]
  74. Pearce, M.M.; Hilt, E.E.; Rosenfeld, A.B.; Zilliox, M.J.; Thomas-White, K.; Fok, C.; Kliethermes, S.; Schreckenberger, P.C.; Brubaker, L.; Gai, X.; et al. The female urinary microbiome: A comparison of women with and without urgency urinary incontinence. mBio 2014, 5, e01283-14. [Google Scholar] [CrossRef] [Green Version]
  75. Baka, S.; Spathi, A.; Tsouma, I.; Kouskouni, E. Symptomatic Shigella sonnei urinary tract infection in pregnancy. Clin. Exp. Obstet. Gynecol. 2013, 40, 116–117. [Google Scholar] [PubMed]
  76. Amabebe, E.; Anumba, D. The vaginal microenvironment: The physiologic role of lactobacilli. Front. Med. 2018, 5, 181. [Google Scholar] [CrossRef] [Green Version]
  77. Stapleton, A.E.; Au-Yeung, M.; Hooton, T.M.; Fredricks, D.N.; Roberts, P.L.; Czaja, C.A.; Yarova-Yarovaya, Y.; Fiedler, T.; Cox, M.; Stamm, W.E. Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection. Clin. Infect. Dis. 2011, 52, 1212–1217. [Google Scholar] [CrossRef] [PubMed]
  78. Butler, D.S.; Silverstroni, A.; Stapleton, A.E. Cytoprotective effect of Lactobacillus crispatus CTV-05 against uropathogenic E. coli. Pathogens 2016, 5, 27. [Google Scholar] [CrossRef] [Green Version]
  79. Lim, I.S.; Lee, H.S.; Kim, W.Y. The effect of lactic acid bacteria isolates on the urinary tract pathogens to infants In vitro. J. Korean Med. Sci. 2009, 24, S57–S62. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Gajer, P.; Brotman, R.M.; Bai, G.; Sakamoto, J.; Schütte, U.M.E.; Zhong, X.; Koenig, S.S.K.; Fu, L.; Ma, Z.; Zhou, X.; et al. Temporal dynamics of the human vaginal microbiota. Sci. Transl. Med. 2012, 4, 132ra52. [Google Scholar] [CrossRef] [Green Version]
  81. Price, T.K.; Wolff, B.; Halverson, T.; Limeira, R.; Brubaker, L.; Dong, Q.; Mueller, E.R.; Wolfe, A.J. Temporal dynamics of the adult female lower urinary tract microbiota. mBio 2020, 11, e00475-20. [Google Scholar] [CrossRef]
  82. Sokol-Leszczynska, B.; Leszczynski, P.; Lachowicz, D.; Rostkowska, O.; Niemczyk, M.; Piecha, T.; van Belkum, A.; Sawicka-Grzelak, A.; Mlynarczyk, G. Corynebac-terium coyleae as potential urinary tract pathogen. Eur. J. Clin. Microbiol. Infect. Dis. 2019, 38, 1339–1342. [Google Scholar] [CrossRef] [Green Version]
  83. Brubaker, L.; Wolfe, A.J. The urinary microbiota: A paradigm shift for bladder disorders? Curr. Opin. Obstet. Gynecol. 2016, 28, 407–412. [Google Scholar] [CrossRef] [Green Version]
  84. Beerepoot, M.A.J.; Geerlings, S.V.; Van Haarst, E.P.; Van Charante, N.M.; Ter Riet, G. Nonantibiotic prophylaxis for recurrent urinary tract infections: A systematic review and meta-analysis of randomized controlled trials. J. Urol. 2013, 190, 1981–1989. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Anger, J.T.; Bixler, B.R.; Holmes, R.S.; Lee, U.J.; Santiago-Lastra, Y.; Selph, S.S. Updates to Recurrent Uncomplicated Urinary Tract Infections in Women: AUA/CUA/SUFU Guideline. J. Urol. 2022, 208, 536–541. [Google Scholar] [CrossRef] [PubMed]
  86. Shafrin, J.; Marijam, A.; Joshi, A.V.; Mitrani-Gold, F.S.; Everson, K.; Tuly, R.; Rosenquist, P.; Gillam, M.; Ruiz, M.E. Impact of suboptimal or inappropriate treatment on healthcare resource use and cost among patients with uncomplicated urinary tract infection: An analysis of integrated delivery network electronic health records. Antimicrob. Resist. Infect. Control. 2022, 11, 133. [Google Scholar] [CrossRef]
  87. Moon, R.C.; Marijam, A.; Mitrani-Gold, F.S.; Gibbons, D.C.; Kartashov, A.; Rosenthal, N.A.; Joshi, A.V. Treatment patterns, healthcare resource use, and costs associated with uncomplicated urinary tract infection among female patients in the United States. PLoS ONE 2022, 17, e0277713. [Google Scholar] [CrossRef]
  88. Linhares, I.; Raposo, T.; Rodrigues, A.; Almeida, A.A.-O. Incidence and diversity of antimicrobial multidrug resistance profiles of uropathogenic bacteria. Biomed. Res. Int. 2015, 2015, 354084. [Google Scholar] [CrossRef] [Green Version]
  89. Mulvey, M.A.; Lopez-Boado, Y.S.; Wilson, C.L.; Roth, R.; Parks, W.C.; Heuser, J.; Hultgren, S.J. Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli. Science 1998, 282, 1494–1497. [Google Scholar] [CrossRef]
  90. Dantas, G.; Sommer, M.O.A.; Oluwasegun, R.D.; Church, G.M. Bacteria Subsisting on Antibiotics. Science 2008, 320, 100–103. [Google Scholar] [CrossRef] [Green Version]
  91. Davies, J.; Davies, D. Origins and Evolution of Antibiotic Resistance. Microbiol. Mol. Biol. Rev. 2010, 74, 417–433. [Google Scholar] [CrossRef] [Green Version]
  92. Gniadkowski, M. Evolution of Extended-Spectrum b-Lactamases by Mutation. Clin. Microbiol. Infect. 2008, 14, 11–32. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Ruiz, C.; Levy, S.B. Many Chromosomal Genes Modulate Mara-Mediated Multidrug Resistance in Escherichia coli. Antimicrob. Agents Chemother. 2010, 54, 2125–2134. [Google Scholar] [CrossRef] [Green Version]
  94. Schuster, S.; Vavra, M.; Schweigger, T.M.; Rossen, J.W.A.; Matsumura, Y.; Kern, W.V. Contribution of AcrAB-TolC to Multidrug Resistance in an Escherichia coli Sequence Type 131 Isolate. Int. J. Antimicrob. Agents 2017, 50, 477–481. [Google Scholar] [CrossRef]
  95. Atac, N.; Kurt-Azap, O.; Dolapci, I.; Yesilkaya, A.; Ergonul, O.; Gonen, M.; Can, F. The Role of AcrAB–TolC Efflux Pumps on Quinolone Resistance of E. coli ST131. Curr. Microbiol. 2018, 75, 1661–1666. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Chowdhury, N.; Suhani, S.; Purkaystha, A.; Begum, M.K.; Raihan, T.; Alam, M.J.; Islam, K.; Azad, A.K. Identification of AcrAB-TolC Efflux Pump Genes and Detection of Mutation in Efflux Repressor AcrR From Omeprazole Responsive Multidrug-Resistant Escherichia coli Isolates Causing Urinary Tract Infections. Microbiol. Insights 2019, 12, 1178636119889629. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Lynch, S.V.; Dixon, L.; Benoit, M.R.; Brodie, E.L.; Keyhan, M.; Hu, P.; Ackerley, D.F.; Andersen, G.L.; Matin, A. Role of the rapA gene in controlling antibiotic resistance of Escherichia coli biofilms. Antimicrob. Agents Chemother. 2007, 51, 3650–3658. [Google Scholar] [CrossRef] [Green Version]
  98. Sharma, G.; Sharma, S.; Sharma, P.; Chandola, D.; Dang, S.; Gupta, S.; Gabrani, R. Escherichia coli Biofilm: Development and Therapeutic Strategies. J. Appl. Microbiol. 2016, 121, 309–319. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  99. Wu, K.H.; Wang, K.C.; Lee, L.W.; Huang, Y.N.; Yeh, K.S. A constitutively mannose-sensitive agglutinating Salmonella enterica subsp. enterica serovar typhimurium strain, carrying a transposon in the fimbrial usher gene stbC, exhibits multidrug resistance and flagellated phenotypes. Sci. World J. 2012, 2012, 280264. [Google Scholar] [CrossRef] [Green Version]
  100. Lee, S.J.; Choe, H.S.; Na, Y.G.; Kim, K.H.; Kim, J.H.; Chung, H.; Chung, J.M.; Jung, J.H.; Choi, H.; Lee, S.-J.; et al. 2017 Guidelines of the Korean association of urogenital tract infection and inflammation: Recurrent urinary tract infection. Urogenit. Tract Infect. 2017, 12, 7–14. [Google Scholar] [CrossRef] [Green Version]
  101. Raz, R.; Stamm, W.E. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N. Engl. J. Med. 1993, 329, 753–756. [Google Scholar] [CrossRef] [Green Version]
  102. Lüthje, P.; Brauner, H.; Ramos, N.L.; Övregaard, A.; Gläser, R.; Hirschberg, A.L.; Aspenström, P.; Brauner, A. Estrogen supports urothelial defense mechanisms. Sci. Transl. Med. 2013, 5, 190ra80. [Google Scholar] [CrossRef]
  103. Lüthje, P.; Hirschberg, A.L.; Brauner, A. Estrogenic action on innate defense mechanisms in the urinary tract. Maturitas 2014, 77, 32–36. [Google Scholar] [CrossRef] [PubMed]
  104. Chen, Y.Y.; Su, T.H.; Lau, H.H. Estrogen for the prevention of recurrent urinary tract infections in postmenopausal women: A meta-analysis of randomized controlled trials. Int. Urogynecol. J. 2021, 32, 17–25. [Google Scholar] [CrossRef]
  105. Leckie, K.J. What is the evidence for the role of oestrogen in the prevention of recurrent urinary tract infections in postmenopausal women? An evidence-based review. J. Clin. Gerontol. Geriatr. 2010, 1, 31. [Google Scholar] [CrossRef] [Green Version]
  106. Dueñas-Garcia, O.F.; Sullivan, G.; Hall, C.D.; Flynn, M.K.; O’Dell, K. Pharmacological agents to decrease new episodes of recurrent lower urinary tract infections in postmenopausal women. A systematic review. Female Pelvic Med. Reconstruct. Surg. 2016, 22, 63–69. [Google Scholar] [CrossRef]
  107. Antoniou, V.; Somani, B.K. Topical and Oral Oestrogen for Recurrent Urinary Tract Infection-Evidence-based Review of Literature, Treatment Recommendations, and Correlation with the European Association of Urology Guidelines on Urological Infections. Eur. Urol. Focus 2022, 8, 1768–1774. [Google Scholar] [CrossRef]
  108. Perrotta, C.; Aznar, M.; Mejia, R.; Albert, X.; Ng, C.W. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database Syst. Rev. 2008, 2, CD005131. [Google Scholar] [CrossRef] [PubMed]
  109. Fractional CO2 Vaginal LASER Therapy for Recurrent Urinary Tract Infection. Available online: https://clinicaltrials.gov/ct2/show/NCT04301934 (accessed on 1 June 2020).
  110. Thomas-White, K.; Forster, S.C.; Kumar, N.; Van Kuiken, M.; Putonti, C.; Stares, M.D.; Hilt, E.E.; Price, T.K.; Wolfe, A.J.; Lawley, T.D. Culturing of female bladder bacteria reveals an interconnected urogenital microbiota. Nat. Commun. 2018, 9, 1557. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  111. Perez-Carrasco, V.; Soriano-Lerma, A.; Soriano, M.; Gutiérrez-Fernández, J.; Garcia-Salcedo, J.A. Urinary Microbiome: Yin and Yang of the Urinary Tract. Front. Cell. Infect. Microbiol. 2021, 11, 617002. [Google Scholar] [CrossRef] [PubMed]
  112. Burton, J.P.; Cadieux, P.A.; Reid, G. Improved understanding of the bacterial vaginal microbiota of women before and after probiotic instillation. Appl. Environ. Microbiol. 2003, 69, 97–101. [Google Scholar] [CrossRef] [Green Version]
  113. Grin, P.; Kowalewska, P.M.; Alhazzan, W.; Fox-Robichaud, A.E. Lactobacillus for preventing recurrent urinary tract infections in women: Meta-analysis. Can. J. Urol. 2013, 20, 6607. [Google Scholar]
  114. Ng, Q.X.; Peters, C.; Venkatanarayanan, N.; Goh, Y.Y.; Ho, C.Y.X.; Yeo, W.-S. Use of Lactobacillus spp. to prevent recurrent urinary tract infections in females. Med. Hypotheses 2018, 114, 49–54. [Google Scholar] [CrossRef]
  115. Emami, E.; Mt Sherwin, C.; Heidari-Soureshjani, S. Effect of probiotics on urinary tract infections in children: A systematic review and meta-analysis. Curr. Rev. Clin. Exp. Pharmacol. 2022. [Google Scholar] [CrossRef] [PubMed]
  116. Abdullatif, V.A.; Sur, R.L.; Eshaghian, E.; Gaura, K.A.; Goldman, B.; Panchatsharam, P.K.; Williams, N.J.; Abbott, J.E. Efficacy of Probiotics as Prophylaxis for Urinary Tract Infections in Premenopausal Women: A Systematic Review and Meta-Analysis. Cureus 2021, 13, e18843. [Google Scholar] [CrossRef]
  117. Canales, J.; Rada, G. Are probiotics effective in preventing urinary tract infection? Medwave 2018, 18, e7186. [Google Scholar] [CrossRef]
  118. Bonkat, G.; Bartoletti, R.; Bruyère, F.; Cai, T.; Geerlings, S.E.; Köves, B.; Schubert, S.; Pilatz, A.; Veeratterapillay, R.; Wagenlehner, F. European Urological Association: Guidelines on Urological Infections. 2022. Available online: https://d56bochluxqnz.cloudfront.net/documents/full-guideline/EAU-Guidelines-on-Urological-Infections-2022.pdf (accessed on 1 March 2022).
  119. Rauf, A.; Imran, M.; Abu-Izneid, T.; Iahtisham-Ul-Haq Patel, S.; Pan, X.; Naz, S.; Sanches Silva, A.; Saeed, F.; Rasul Suleria, H.A. Proanthocyanidins: A comprehensive review. Biomed. Pharmacother. 2019, 116, 108999. [Google Scholar] [CrossRef]
  120. Foo, L.Y.; Lu, Y.; Howell, A.B.; Vorsa, N. A-type proanthocyanidin trimers from cranberry that inhibit adherence of uropathogenic P-fimbriated Escherichia coli. J. Nat. Prod. 2000, 63, 1225–1228. [Google Scholar] [CrossRef] [PubMed]
  121. Hidalgo, G.; Chan, M.; Tufenkji, N. Inhibition of Escherichia coli CFT073 fliC expression and motility by cranberry materials. Appl. Environ. Microbiol. 2011, 77, 6852–6857. [Google Scholar] [CrossRef] [Green Version]
  122. O’May, C.; Tufenkji, N. The swarming motility of Pseudomonas aeruginosa is blocked by cranberry proanthocyanidins and other tannin-containing materials. Appl. Environ. Microbiol. 2011, 77, 3061–3067. [Google Scholar] [CrossRef] [Green Version]
  123. Vasudevan, S.; Thamil Selvan, G.; Bhaskaran, S.; Hari, N.; Solomon, A.P. Reciprocal Cooperation of Type A Procyanidin and Nitrofurantoin Against Multi-Drug Resistant (MDR) UPEC: A pH-Dependent Study. Front. Cell Infect. Microbiol. 2020, 10, 421. [Google Scholar] [CrossRef] [PubMed]
  124. Scharf, B.; Sendker, J.; Dobrindt, U.; Hensel, A. Influence of cranberry extract on tamm-horsfall protein in human urine and its antiadhesive activity against uropathogenic Escherichia coli. Planta Med. 2019, 85, 126–138. [Google Scholar] [CrossRef]
  125. Scharf, B.; Schmidt, T.J.; Rabbani, S.; Stork, C.; Dobrindt, U.; Sendker, J.; Ernst, B.; Hensel, A. Antiadhesive natural products against uropathogenic E. coli: What can we learn from cranberry extract? J. Ethnopharmacol. 2020, 257, 112889. [Google Scholar] [CrossRef]
  126. Maisuria, V.B.; Okshevsky, M.; Déziel, E.; Tufenkji, N. Proanthocyanidin interferes with intrinsic antibiotic resistance mechanisms of gram-negative bacteria. Adv. Sci. 2019, 6, 1802333. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Vasudevan, S.; Swamy, S.S.; Kaur, G.; Princy, S.A.; Balamurugan, P. Synergism between quorum sensing inhibitors and antibiotics: Combating the antibiotic resistance crisis. In Biotechnological Applications of Quorum Sensing Inhibitors; Kalia, V.C., Ed.; Springer: Singapore, 2018; pp. 205–225. [Google Scholar] [CrossRef]
  128. Jepson, R.G.; Williams, G.; Craig, J.C. Cranberries for preventing urinary tract infections. Cochrane Database Syst. Rev. 2012, 10, CD001321. [Google Scholar] [CrossRef] [Green Version]
  129. Fu, Z.; Liska, D.; Talan, D.; Chung, M. Cranberry Reduces the Risk of Urinary Tract Infection Recurrence in Otherwise Healthy Women: A Systematic Review and Meta-Analysis. J. Nutr. 2017, 147, 2282–2288. [Google Scholar] [CrossRef] [Green Version]
  130. Luís, Â.; Domingues, F.; Pereira, L. Can Cranberries Contribute to Reduce the Incidence of Urinary Tract Infections? A Systematic Review with Meta-Analysis and Trial Sequential Analysis of Clinical Trials. J. Urol. 2017, 198, 614–621. [Google Scholar] [CrossRef] [PubMed]
  131. Wang, C.H.; Fang, C.C.; Chen, N.C.; Liu, S.S.H.; Yu, P.H.; Wu, T.Y.; Chen, W.-T.; Lee, C.C.; Chen, S.C. Cranberry-containing products for prevention of urinary tract infections in susceptible populations: A systematic review and meta-analysis of randomized controlled trials. Arch. Intern. Med. 2012, 172, 988–996. [Google Scholar] [CrossRef] [Green Version]
  132. Tambunan, M.P.; Rahardjo, H.E. Cranberries for women with recurrent urinary tract infection: A meta-analysis. Med. J. Indones. 2019, 28, 268–275. [Google Scholar] [CrossRef]
  133. Liska, D.J.; Kern, H.J.; Maki, K.C. Cranberries and Urinary Tract Infections: How Can the Same Evidence Lead to Conflicting Advice? Adv. Nutr. 2016, 7, 498–506. [Google Scholar] [CrossRef] [Green Version]
  134. Han, Z.; Pinkner, J.S.; Ford, B.; Chorell, E.; Crowley, J.M.; Cusumano, C.K.; Campbell, S.; Henderson, J.P.; Hultgren, S.J.; Janetka, J.W. Lead optimization studies on FimH antagonists: Discovery of potent and orally bioavailable ortho-substituted biphenyl mannosides. J. Med. Chem. 2012, 55, 3945–3959. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Han, Z.; Pinkner, J.S.; Ford, B.; Obermann, R.; Nolan, W.; Wildman, S.A.; Hobbs, D.; Ellenberger, T.; Cusumano, C.K.; Hultgren, S.J.; et al. Structure-based drug design and optimization of mannoside bacterial FimH antagonists. J. Med. Chem. 2010, 53, 4779–4792. [Google Scholar] [CrossRef] [Green Version]
  136. Cusumano, C.K.; Pinkner, J.S.; Han, Z.; Greene, S.A.; Ford, B.A.; Crowley, J.R.; Henderson, J.P.; Janetka, J.W.; Hultgren, S.J. Treatment and prevention of urinary tract infection with orally active FimH inhibitors. Sci. Transl. Med. 2011, 3, 109–115. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Klein, T.; Abgottspon, D.; Wittwer, M.; Rabbani, S.; Herold, J.; Jiang, X.; Kleeb, S.; Luthi, C.; Scharenberg, M.; Bezenuon, J.; et al. FimH antagonists for the oral treatment of urinary tract infections: From design and synthesis to in vitro and in vivo evaluation. J. Med. Chem. 2010, 53, 8627–8641. [Google Scholar] [CrossRef]
  138. Guiton, P.S.; Cusumano, C.K.; Kline, K.A.; Dodson, K.W.; Han, Z.; Janetka, J.W.; Henderson, J.P.; Caparon, M.G.; Hultgren, S.J. Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice. Antimicrob. Agents Chemother. 2012, 56, 4738–4745. [Google Scholar] [CrossRef] [Green Version]
  139. Totsika, M.; Kostakioti, M.; Hannan, T.J.; Upton, M.; Beatson, S.A.; Janetka, J.W.; Hultgren, S.J.; Schembri, M.A. A FimH inhibitor prevents acute bladder infection and treats chronic cystitis caused by multidrug-resistant uropathogenic Escherichia coli ST131. J. Infect. Dis. 2013, 208, 921–928. [Google Scholar] [CrossRef] [Green Version]
  140. Kranz, J.; Schmidt, S.; Schneidewind, L. Current Evidence on Nonantibiotic Prevention of Recurrent Urinary Tract Infections. Eur. Urol. Focus 2019, 5, 17–19. [Google Scholar] [CrossRef] [PubMed]
  141. Lenger, S.; Bradley, M.S.; Thomas, D.A.; Bertolet, M.H.; Lowder, J.L.; Sutcliffe, S. D-mannose vs other agents for recurrent urinary tract infection prevention in adult women: A systematic review and meta-analysis. Am. J. Obstet. Gynecol. 2020, 223, 265. [Google Scholar] [CrossRef] [PubMed]
  142. Ala-Jaakkola, R.; Laitila, A.; Ouwehand, A.C.; Lehtoranta, L. Role of D-mannose in urinary tract infections—A narrative review. Nutr. J. 2022, 21, 18. [Google Scholar] [CrossRef] [PubMed]
  143. Kyriakides, R.; Jones, P.; Somani, B.K. Role of D-Mannose in the Prevention of Recurrent Urinary Tract Infections: Evidence from a Systematic Review of the Literature. Eur. Urol. Focus 2021, 7, 1166–1169. [Google Scholar] [CrossRef]
  144. Damiano, R.; Quarto, G.; Bava, I.; Ucciero, G.; De Domenico, R.; Palumbo, M.I.; Autorino, R. Prevention of recurrent urinary tract infections by intravesical administration of hyaluronic acid and chondroitin sulphate: A placebo-controlled randomised trial. Eur. Urol. 2011, 59, 645, Corrigendum in Eur. Urol. 2011, 60, 193. [Google Scholar] [CrossRef]
  145. De Vita, D.; Giordano, S. Effectiveness of intravesical hyaluronic acid/chondroitin sulfate in recurrent bacterial cystitis: A randomized study. Int. Urogynecol. J. 2012, 23, 1707–1713. [Google Scholar] [CrossRef]
  146. Goddard, J.C.; Janssen, D.A.W. Intravesical hyaluronic acid and chondroitin sulfate for recurrent urinary tract infections: Systematic review and meta-analysis. Int. Urogynecol. J. 2018, 29, 933–942. [Google Scholar] [CrossRef] [Green Version]
  147. Lee, B.S.B.; Bhuta, T.; Simpson, J.M.; Craig, J. Methenamine hippurate for preventing urinary tract infections. Cochrane Database Syst. Rev. 2012, 10, CD003265. [Google Scholar] [CrossRef]
  148. Bakhit, M.; Krzyzaniak, N.; Hilder, J.; Clark, J.; Scott, A.M.; Del Mar, C. Use of methenamine hippurate to prevent urinary tract infections in community adult women: A systematic review and meta-analysis. Br. J. Gen. Pract. 2021, 71, e528. [Google Scholar] [CrossRef]
  149. Harding, C.; Mossop, H.; Homer, T.; Chadwick, T.; King, W.; Carnell, S.; Lecouturier, J.; Abouhajar, A.; Vale, L.; Watson, G.; et al. Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: Multicentre, open label, randomised, non-inferiority trial. BMJ 2022, 376, e068229. [Google Scholar] [CrossRef]
  150. Botros, C.; Lozo, S.; Iyer, S.; Warren, A.; Goldberg, R.; Tomezsko, J.; Sasso, K.; Sand, P.; Gafni-Kane, A.; Biener, A.; et al. Methenamine hippurate compared with trimethoprim for the prevention of recurrent urinary tract infections: A randomized clinical trial. Int. Urogynecol. J. 2022, 33, 571–580. [Google Scholar] [CrossRef] [PubMed]
  151. Dinarello, C.A. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol. Rev. 2018, 281, 8–27. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Chancellor, M.B.; Lamb, L.E.; Ward, E.P.; Bartolone, S.N.; Carabulea, A.; Sharma, P.; Janicki, J.; Smith, C.; Laudano, M.; Abraham, N.; et al. Comparing concentration of urinary inflammatory cytokines in interstitial cystitis, overactive bladder, urinary tract infection, and bladder cancer. Urol. Sci. 2022, 33, 199–204. [Google Scholar] [CrossRef]
  153. Mayer-Barber, K.D.; Andrade, B.B.; Barber, D.L.; Hieny, S.; Feng, C.; Caspar, P.; Oland, S.; Gordon, S.; Sher, A. Innate and adaptive interferons suppress IL-1α and IL-1β production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection. Immunity 2011, 35, 1023–1034. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Tang, A.; Sharma, A.; Jen, R.; Hirschfeld, A.F.; Chilvers, M.; Lavoie, P.M.; Turvey, S.E. Inflammasome- mediated IL-1β production in humans with cystic fibrosis. PLoS ONE 2012, 7, e37689. [Google Scholar] [CrossRef] [Green Version]
  155. Huet, T.; Beaussier, H.; Voisin, O.; Jouveshomme, S.; Dauriat, G.; Lazareth, I.; Sacco, E.; Naccache, J.-M.; Bézie, Y.; Laplanche, S.; et al. Anakinra for severe forms of COVID-19:a cohort study. Lancet Rheumatol. 2020, 2, e393–e400. [Google Scholar] [CrossRef]
  156. Iannitti, R.G.; Napolioni, V.; Oikonomou, V.; De Luca, A.; Galosi, C.; Pariano, M.; Massi-Benedetti, C.; Borghi, M.; Puccetti, M.; Lucidi, V.; et al. IL-1 receptor antagonist ameliorates inflammasome- dependent inflammation in murine and human cystic fibrosis. Nat. Commun. 2016, 7, 10791. [Google Scholar] [CrossRef] [Green Version]
  157. Kyriazopoulou, E.; Huet, T.; Cavalli, G.; Gori, A.; Kyprianou, M.; Pickkers, P.; Eugen-Olsen, J.; Clerici, M.; Veas, F.; Chatellier, G.; et al. Effect of anakinra on mortality in patients with COVID-19: A systematic review and patient- level meta- analysis. Lancet Rheumatol. 2021, 3, e690–e697. [Google Scholar] [CrossRef] [PubMed]
  158. Klemm, P.; Schembri, M.A. Fimbriae-assisted bacterial surface display of heterologous peptides. Int. J. Med. Microbiol. 2000, 290, 215–221. [Google Scholar] [CrossRef]
  159. Goluszko, P.; Goluszko, E.; Nowicki, B.; Nowicki, S.; Popo, V.; Wang, H.Q. Vaccination with purified Dr fimbraie reduces mortality associated with chronic urinary tract infection due to Escherichia coli bearing Dr adhesin. Infect. Immun. 2005, 73, 627–631. [Google Scholar] [CrossRef] [Green Version]
  160. Asadi Karam, M.R.; Oloomi, M.; Mahdavi, M.; Habibi, M.; Bouzari, S. Vaccination with recombinant FimH fused with flagellin enhances cellular and humoral immunity against urinary tract infection in mice. Vaccine 2013, 31, 1210–1216. [Google Scholar] [CrossRef] [PubMed]
  161. Langermann, S.; Palaszynski, S.; Barnhart, M.; Auguste, G.; Pinkner, J.S.; Burlein, J.; Barren, P.; Koenig, S.; Leath, S.; Jones, C.H.; et al. Prevention of mucosal Escherichia coli infection by FimH-adhesin-based systemic vaccination. Science 1997, 276, 607–611. [Google Scholar] [CrossRef] [PubMed]
  162. Savar, N.S.; Jahanian-Najafabadi, A.; Mahdavi, M.; Shokrgozar, M.A.; Jafari, A.; Bouzari, S. In silico and in vivo studies of truncated forms of flagellin (FliC) of enteroaggregative Escherichia coli fused to FimH from uropathogenic Escherichia coli as a vaccine candidate against urinary tract infections. J. Biotechnol. 2014, 175, 31–37. [Google Scholar] [CrossRef]
  163. Eldridge, G.R.; Hughey, H.; Rosenberger, L.; Martin, S.M.; Shapiro, A.M.; D’Antonio, E.; Krejci, K.G.; Shore, N.; Peterson, J.; Lukes, A.S.; et al. Safety and immunogenicity of an adjuvanted Escherichia coli adhesin vaccine in healthy women with and without histories of recurrent urinary tract infections: Results from a first-in-human phase 1 study. Hum. Vaccin. Immunother. 2021, 17, 1262–1270. [Google Scholar] [CrossRef] [PubMed]
  164. Naber, K.G.; Cho, Y.H.; Matsumoto, T.; Schaeffer, A.J. Immunoactive prophylaxis of recurrent urinary tract infections: A meta-analysis. Int. J. Antimicrob. Agents 2009, 33, 111–119. [Google Scholar] [CrossRef]
  165. Aziminia, N.; Hadjipavlou, M.; Philippou, Y.; Pandian, S.S.; Malde, S.; Hammadeh, M.Y. Vaccines for the prevention of recurrent urinary tract infections: A systematic review. BJU Int. 2019, 123, 753–768. [Google Scholar] [CrossRef] [Green Version]
  166. Prattley, S.; Geraghty, R.; Moore, M.; Somani, B.K. Role of Vaccines for Recurrent Urinary Tract Infections: A Systematic Review. Eur. Urol. Focus 2020, 6, 593–604. [Google Scholar] [CrossRef] [PubMed]
  167. O’Hanley, P.; Lalonde, G.; Ji, G. Alpha-hemolysin contributes to the pathogenicity of piliated digalactoside-binding Escherichia coli in the kidney: Efficacy of an α-hemolysin vaccine in preventing renal injury in the BALB/c mouse model of pyelonephritis. Infect. Immun. 1991, 59, 1153–1161. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  168. Alamuri, P.; Eaton, K.A.; Himpsl, S.D.; Smith, S.N.; Mobley, H.L. Vaccination with proteus toxic agglutinin, a hemolysin-independent cytotoxin in vivo, protects against Proteus mirabilis urinary tract infection. Infect. Immun. 2009, 77, 632–641. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  169. Brumbaugh, A.R.; Smith, S.N.; Mobley, H.L. Immunization with the yersiniabactin receptor, FyuA, protects against pyelonephritis in a murine model of urinary tract infection. Infect. Immun. 2013, 81, 3309–3316. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  170. Alteri, C.J.; Hagan, E.C.; Sivick, K.E.; Smith, S.N.; Mobley, H.L. Mucosal immunization with iron receptor antigens protects against urinary tract infection. PLoS Pathog. 2009, 5, e1000586. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Ijms 24 07055 g001 550
Figure 1. The invasive process of uropathogenic Escherichia coli into the uroepithelium.
Figure 1. The invasive process of uropathogenic Escherichia coli into the uroepithelium.
Ijms 24 07055 g001
Ijms 24 07055 g002 550
Figure 2. Potential antivirulence intervention for uropathogenic Escherichia coli. Schematic diagram illustrating alternative treatment options, including prophylactic strategies, antiadhesive treatments, immunomodulation therapy, and potential vaccines, that target the virulence of uropathogenic Escherichia coli.
Figure 2. Potential antivirulence intervention for uropathogenic Escherichia coli. Schematic diagram illustrating alternative treatment options, including prophylactic strategies, antiadhesive treatments, immunomodulation therapy, and potential vaccines, that target the virulence of uropathogenic Escherichia coli.
Ijms 24 07055 g002
Table
Table 1. Common strains of UPEC used in UTI studies with different serogroups.
Table 1. Common strains of UPEC used in UTI studies with different serogroups.
StrainSerotypeIron Uptake SystemSourceCharacteristicsReference
536O6:K15:H31Yersiniabactin, enterobactin, salmochelin, and hemin uptake system From a patient with acute pyelonephritisIncreased hemolytic activity (stronger than CFT073) [15,16]
CFT073O6:K2:H1Enterobactin, salmochelin, aerobactin, hemin uptake system, and iron/manganese transportBlood and urine of hospitalized women with acute pyelonephritisIncreased hemolytic activity. Encoding a gene cluster (c1931-c1936), that can produce F9 fimbria [17,18]
UTI89O18:K1:H17Yersiniabactin, enterobactin, salmochelin, hemin uptake system, and iron/manganese transportUrine of a patient with acute cystitisDecreased endogenous production of ROS 1
Multiple genes related to biofilm formation were identified		 [13,19]
F11O139:H38FetMP systemFrom a patient with acute uncomplicated cystitis and bacteriuriaAble to use both oxidation states of iron efficiently under conditions of ever-changing Fe(II)/Fe(III) ratios, aiding in colonization of the urinary tract [20]
ABU83972Ont:K5Yersiniabactin, enterobactin, salmochelin, aerobactin, hemin uptake system, and iron/manganese transportUrine of a female patient with asymptomatic bacteriuriaRapid growth in urine [20]
1 ROS = reactive oxygen species.
Table
Table 2. Various adhesive fimbriae, toxins, and autotransporters contributing to virulence in UPEC.
Table 2. Various adhesive fimbriae, toxins, and autotransporters contributing to virulence in UPEC.
Virulence FactorsType of Virulence Factors ReceptorGeneCharacteristicsReference
AdhesinsType I fimbriaeMonomannose moiety of the tetraspanin molecule uroplakin 1a (UP1a) fim B, fim E, fim H, and Pil. Mannose-sensitive
. Responsible for colonization, invasion, and persistence of uroepithelial cells
. The most frequently expressed virulence factor, accounting for 80 to 100% of UPEC
. Less prevalent in pyelonephritogenic UPEC but prevalent in urinary catheter-related bacteria		 [27,28]
P fimbriaeGloboseries glycosphingolipid receptors (Gal-Gal)PapG and papGAP. Mannose-insensitive
. Able to bind to glycosphingolipids of the kidney epithelium
. A super-virulence factor that transits the response from asymptomatic bacteriuria to acute pyelonephritis in the host
. Associated with the severity of UTI		 [29,30]
Dr adhesinsType 4 collagen and Dr blood group antigenAfaE1–5, AfaF, and Drb
operon		. Invasion of epithelial cells of the bladder
. Consists of both fimbrial and afimbrial adhesins		 [28]
S and F1C fimbriaeSialyl-α-2-3 galactosideSfa/fac. Associated with pyelonephritis and cystitis
. Expressed by approximately 14% of UPEC		 [31,32]
Toxinsα-hemolysin (HlyA)CD11a/CD18 (LFA-1) and glycophorinhly. Isolated from more than 70% of patients with pyelonephritis
. Isolated from 31–48% of patients with acute cystitis
. Associated with renal complications, including permanent renal scarring, in up to 50% of pyelonephritis cases		 [33]
Cytotoxic necrotizing factor 1Lu/BCAM adhesion glycoprotein cnf1. Able to modulate the activity of Rho GTPases [34,35,36]
AutotransportersVacuolating autotransporter toxin (VAT)Cytokeratin 8vat. Identified in 20–36% of UPEC
. Isolated from 59–68% of patients with pyelonephritis and urosepsis		 [24,37,38,39,40]
Secreted autotransporter toxin (SAT)Cytokeratin 8 Sat-encoding gene (sat). Isolated from 68% of patients with pyelonephritis [40]
Table
Table 3. Mechanisms of survival of UPEC within urothelial cells.
Table 3. Mechanisms of survival of UPEC within urothelial cells.
Aim of UPECStrategies of UPECMechanismReference
Antagonism of uroepithelial cell apoptosisAerobic respirationCytochrome bd (reducing the efficiency of mitochondrial respiration) → stabilize HIF-1 → promote aerobic glycolysis [43]
Maintenance of uropathogens’ cellular function Nutrient acquisitionIron: extracellular insoluble/biounavailable Fe3+ + siderophore → soluble/bioavailable siderophore- Fe3+ complex → transport into cell → intracellular iron assimilation from the siderophore–Fe3+ complex → intracellular iron usage and storage [46]
Enhancement of uroepithelial cell exfoliationToxin secretionToxins → cell damage and apoptosis→ release of iron and nutrients from host cells [14]
Table
Table 4. The pathogenesis and defenses of the host with regard to acute cystitis and potential treatment strategies.
Table 4. The pathogenesis and defenses of the host with regard to acute cystitis and potential treatment strategies.
Steps of UPEC PathogenesisNormal Defenses of Hosts
Colonization of uropathogens in the urethra, periurethra, and vagina
  • Normal commensal flora form a barrier against the colonization of uropathogens
  • The natural flow of urine with high osmolality and low pH and containing soluble IgA immunoglobulins or Tamm–Horsfall protein (uromodulin)
Fim-H-mediated adherence to epithelial cells of the bladder
  • Inflammatory responses in the lower urinary tract
  • Induction of bacterial clearance by purging the infected uroepithelial cells, which undergo rapid cell death and exfoliation [47]
Biofilm elaboration and intracellular replication
  • Urothelial exfoliation
  • Active expulsion of UPEC by increased intracellular cyclic AMP in urothelial cells [48,49]
Formation of bladder intracellular bacterial communities for invasion and replication
  • Autophagy for the elimination of uropathogens from infected host cells
Siderophores for iron acquisition to maintain survival
  • Host neutrophils produce lipocalin-2 capable of binding enterobactin siderophore against enterobactin-mediated iron uptake by UPEC
Zinc acquisition to maintaining survival
  • Host neutrophil-derived protein calprotein enables the sequestration of zinc
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Chen, Y.-C.; Lee, W.-C.; Chuang, Y.-C. Emerging Non-Antibiotic Options Targeting Uropathogenic Mechanisms for Recurrent Uncomplicated Urinary Tract Infection. Int. J. Mol. Sci. 2023, 24, 7055. https://doi.org/10.3390/ijms24087055

AMA Style

Chen Y-C, Lee W-C, Chuang Y-C. Emerging Non-Antibiotic Options Targeting Uropathogenic Mechanisms for Recurrent Uncomplicated Urinary Tract Infection. International Journal of Molecular Sciences. 2023; 24(8):7055. https://doi.org/10.3390/ijms24087055

Chicago/Turabian Style

Chen, Yu-Chen, Wei-Chia Lee, and Yao-Chi Chuang. 2023. "Emerging Non-Antibiotic Options Targeting Uropathogenic Mechanisms for Recurrent Uncomplicated Urinary Tract Infection" International Journal of Molecular Sciences 24, no. 8: 7055. https://doi.org/10.3390/ijms24087055

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop