Treatment and Prevention of Urinary Tract Infection with Orally Active FimH Inhibitors

Cusumano, Corinne K.; Pinkner, Jerome S.; Han, Zhenfu; Greene, Sarah E.; Ford, Bradley; Crowley, Jan R.; Henderson, Jeffrey P.; Janetka, James W.; Hultgren, Scott J.

doi:10.1126/scitranslmed.3003021

Cited by 286 publications

(298 citation statements)

References 60 publications

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“…These and other considerations have generated an increased interest in the development of non-biocidal anti-infective strategies as alternatives to antibiotics, as these would be expected to show reduced tendency to provoke the appearance of resistant strains. [6][7][8][9][10][11][12][13] One such approach is the development of a † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4nr05906a ‡ These authors contributed equally to the work.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of type 1 fimbriae-mediated Escherichia coli adhesion and biofilm formation by trimeric cluster thiomannosides conjugated to diamond nanoparticles

et al. 2015

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Inhibition of type 1 fi mbriae-mediated Escherichia coli adhesion and biofi lm formation by trimeric cluster thiomannosides conjugated to diamond nanoparticles Trimeric thiosugar clusters, conveniently obtained through a thiol-ene "click" strategy, have been effi ciently conjugated to alkynyl-functionalized nanodiamonds (NDs) using a Cu(I)-catalysed "click" reaction. These tri-thiomannoside clusterconjugated NDs (ND-Man 3 ) are shown to be potent inhibitors of type 1 fi mbriae-mediated E. coli adhesion to yeast and T24 bladder cells and moreover to inhibit E. coli-mediated biofi lm formation. This latter feature has only rarely been reported in the past for analogues featuring such simple multivalent glycosidic motifs and would constitute a useful additional characteristic of any anti-adhesive drug lead. anti-adhesive nanoparticles displaying activity against biofilms. In this work, trimeric thiomannoside clusters conjugated to nanodiamond particles (ND) were targeted for investigation. NDs have attracted attention as a biocompatible nanomaterial and we were curious to see whether the high mannose glycotope density obtained upon grouping monosaccharide units in triads might lead to the corresponding NDconjugates behaving as effective inhibitors of E. coli type 1 fimbriae-mediated adhesion as well as of biofilm formation. The required trimeric thiosugar clusters were obtained through a convenient thiol-ene "click" strategy and were subsequently conjugated to alkynyl-functionalized NDs using a Cu(I)-catalysed "click" reaction. We demonstrated that the tri-thiomannoside cluster-conjugated NDs (ND-Man 3 ) show potent inhibition of type 1 fimbriae-mediated E. coli adhesion to yeast and T24 bladder cells as well as of biofilm formation. The biofilm disrupting effects demonstrated here have only rarely been reported in the past for analogues featuring such simple glycosidic motifs. Moreover, the finding that the tri-thiomannoside cluster (Man 3 N 3 ) is itself a relatively efficient inhibitor, even when not conjugated to any ND edifice, suggests that alternative mono-or multivalent sugar-derived analogues might also be usefully explored for E. coli-mediated biofilm disrupting properties.

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Section: Introductionmentioning

confidence: 99%

Inhibition of type 1 fimbriae-mediated Escherichia coli adhesion and biofilm formation by trimeric cluster thiomannosides conjugated to diamond nanoparticles

et al. 2015

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“…Also, methyl alpha-mannoside was reported to inhibit E. coli and Salmonella binding to glycoprotein CEACAM in vitro [78]. Also, selective FimH-binding mannosides have been indicated in preventing UTIs in a preclinical murine model [106]. In vitro studies have found that anti-CEACAM antibodies block the adhesion of M. catarrhalis, N. meningitidis and NTHi to airway epithelial cells [39,71,107].…”

Section: Inhibiting Specific Bacterial Adhesin-host Receptor Interactmentioning

confidence: 99%

Temporal upregulation of host surface receptors provides a window of opportunity for bacterial adhesion and disease

Shukla

Walters

et al. 2017

Microbiology

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Host surface receptors provide bacteria with a foothold from which to attach, colonize and, in some cases, invade tissue and elicit human disease. In this review, we discuss several key host receptors and cognate adhesins that function in bacterial pathogenesis. In particular, we examine the elevated expression of host surface receptors such as CEACAM-1, CEACAM-6, ICAM-1 and PAFR in response to specific stimuli. We explore how upregulated receptors, in turn, expose the host to a range of bacterial infections in the respiratory tract. It is apparent that exploitation of receptor induction for bacterial adherence is not unique to one body system, but is also observed in the central nervous, gastrointestinal and urogenital systems. Prokaryotic pathogens which utilize this mechanism for their infectivity include Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis and Escherichia coli. A number of approaches have been used, in both in vitro and in vivo experimental models, to inhibit bacterial attachment to temporally expressed host receptors. Some of these novel strategies may advance future targeted interventions for the prevention and treatment of bacterial disease.

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“…α-d-Mannopyranosides tested in the UTI mouse model. Methyl and n-heptyl α-dmannopyranosides 1a and 1b, [7][8][9] biphenyl α-d-mannopyranoside 2a and 2b, [9] diamidobiphenyl α-d-mannopyranoside 3a and 3b [10] and monoamidobiphenyl α-d-mannopyranoside 4.…”

Section: Upia Type 1pilimentioning

confidence: 99%

“…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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Treatment and Prevention of Urinary Tract Infection with Orally Active FimH Inhibitors

Cited by 286 publications

References 60 publications

Inhibition of type 1 fimbriae-mediated Escherichia coli adhesion and biofilm formation by trimeric cluster thiomannosides conjugated to diamond nanoparticles

Inhibition of type 1 fimbriae-mediated Escherichia coli adhesion and biofilm formation by trimeric cluster thiomannosides conjugated to diamond nanoparticles

Temporal upregulation of host surface receptors provides a window of opportunity for bacterial adhesion and disease

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

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