FimH Antagonists for the Oral Treatment of Urinary Tract Infections: From Design and Synthesis to in Vitro and in Vivo Evaluation

Klein, Tobias; Abgottspon, Daniela; Wittwer, Matthias; Rabbani, Said; Herold, Janno; Jiang, Xiaohua; Kleeb, Simon; Lüthi, Christine; Scharenberg, Meike; Bezençon, Jacqueline; Gubler, E.; Pang, Lijuan; Smieško, Martin; Cutting, Brian; Schwardt, Oliver; Ernst, Beat

doi:10.1021/jm101011y

Cited by 188 publications

(206 citation statements)

References 68 publications

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“…1. Timeline of the major steps of the development of antibiotics (top [4] ) and the FimH antiadhesion therapy for the treatment of UTI (bottom [5][6][7][8][9][10] ).…”

Section: Antibiotics and Resistance -The Microbiological Tw Insmentioning

confidence: 99%

In vivo Evaluation of FimH Antagonists – A Novel Class of Antimicrobials for the Treatment of Urinary Tract Infection

Abgottspon¹,

Ernst

2012

Chimia

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The discovery of antimicrobials as β-lactam antibiotics or aminoglycosides revolutionized the treatment of infectious diseases. However, the extensive use rapidly created the problem of resistant pathogens, which are increasingly difficult to treat. FimH antagonists are a new class of antimicrobials, which target the bacterial adhesion to urothelial cells, a crucial first step in the establishment of urinary tract infections. Because of their different mode of action, FimH antagonists neither kill nor inhibit the growth of bacteria, they should have a reduced potential to generate resistant strains. This mini-review outlines the main problems associated with increasing development of antimicrobial resistance. Furthermore, it summarizes the currently available in vivo studies in mice for the treatment of urinary tract infections conducted with FimH antagonists.

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“…1. Timeline of the major steps of the development of antibiotics (top [4] ) and the FimH antiadhesion therapy for the treatment of UTI (bottom [5][6][7][8][9][10] ).…”

Section: Antibiotics and Resistance -The Microbiological Tw Insmentioning

confidence: 99%

In vivo Evaluation of FimH Antagonists – A Novel Class of Antimicrobials for the Treatment of Urinary Tract Infection

Abgottspon¹,

Ernst

2012

Chimia

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“…These structures are key to infection and have been targeted in the development of new therapeutics 21. However, initial strategies employing a vaccine approach and whole pili immunogens have proven ineffective, and other methodologies including the use of a FimC‐FimH complex, UPEC toxins and siderophores have reduced, but not totally inhibited, UPEC infection of the bladder 22, 23, 24. In contrast, agents called mannosides, which function as FimH antagonists and reduce bacterial attachment, show strong potential, with in vivo approaches involving animal models demonstrating the efficacy of a new class, the C ‐mannosides 25.…”

Section: Introductionmentioning

confidence: 99%

High molecular weight hyaluronic acid: a two‐pronged protectant against infection of the urogenital tract?

et al. 2018

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ObjectivesRecurrent urinary tract infections are associated with uropathogenic Escherichia coli (UPEC) ascending and infecting the urinary tract. Antibiotics provide only symptomatic relief, not prevent recurrence. Clinical evidence suggests that intravesical glycosaminoglycan therapy, such as hyaluronic acid (HA), helps reduce UTI recurrence. This has been investigated here using in vitro systems modelling the urogenital tract tissues.Methods RT4 bladder cells were preconditioned with high molecular weight HA (> 1500 kDa) at 2 mg mL−1 and challenged with UPEC to analyse barrier protection and bacterial adherence. Untreated and HA‐preconditioned VK2 E6/E7 vaginal cells were challenged with E. coli flagellin (50 ng mL−1) to mimic bacterial challenge, and media analysed for lipocalin‐2, human β‐defensin 2 and interleukin‐8 by ELISA. Experiments were repeated after siRNA knockdown of Toll‐like receptors 2, 4 and 5, and CD44 to investigate signalling.ResultsMicroscopic analyses showed reduced bacterial adherence and urothelial disruption with HA, suggesting that HA functions as a barrier protecting the epithelium from bacterial infection. Cells treated with HA and flagellin simultaneously produced more of the host antimicrobial peptide LCN2 and pro‐inflammatory IL‐8 (P < 0.05) compared to the no HA/flagellin challenges. Increased gene expression of DEFB4 (P < 0.05), but not the hBD2 peptide, was observed in the HA/flagellin‐challenged cells.ConclusionThese data suggest that exogenous HA has potential to protect the urogenital epithelia from UPEC infection via a two‐pronged approach that involves the physical enhancement of the epithelial barrier and augmentation of its innate immune response.

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“…The development of such antibiotics against pili is still in its infancy, because the structure determination of membrane proteins is still a challenging though quickly growing field. However, there have been some successful attempts to inhibit pilus formation and these follow two main strategies, as reviewed in [66]: (i) competitive inhibition of the adhesive structures such as the mannosides [67,68] and globosides [69] and (ii) inhibition of the assembly pathway. The pilicides developed in Pinkner et al [70] and Chorell et al [71] directly target the UBS-the surface of the chaperone interacting with the NTD, where the proline lock is located.…”

Section: Resultsmentioning

confidence: 99%

Molecular mechanism of bacterial type 1 and P pili assembly

Büsch

Phan

Waksman

2015

Phil. Trans. R. Soc. A.

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The formation of adhesive surface structures called pili or fimbriae (‘bacterial hair’) is an important contributor towards bacterial pathogenicity and persistence. To fight often chronic or recurrent bacterial infections such as urinary tract infections, it is necessary to understand the molecular mechanism of the nanomachines assembling such pili. Here, we focus on the so far best-known pilus assembly machinery: the chaperone–usher pathway producing the type 1 and P pili, and highlight the most recently acquired structural knowledge. First, we describe the subunits' structure and the molecular role of the periplasmic chaperone. Second, we focus on the outer-membrane usher structure and the catalytic mechanism of usher-mediated pilus biogenesis. Finally, we describe how the detailed understanding of the chaperone–usher pathway at a molecular level has paved the way for the design of a new generation of bacterial inhibitors called ‘pilicides’.

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FimH Antagonists for the Oral Treatment of Urinary Tract Infections: From Design and Synthesis to in Vitro and in Vivo Evaluation

Cited by 188 publications

References 68 publications

In vivo Evaluation of FimH Antagonists – A Novel Class of Antimicrobials for the Treatment of Urinary Tract Infection

In vivo Evaluation of FimH Antagonists – A Novel Class of Antimicrobials for the Treatment of Urinary Tract Infection

High molecular weight hyaluronic acid: a two‐pronged protectant against infection of the urogenital tract?

Molecular mechanism of bacterial type 1 and P pili assembly

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