Dataset Information

Comparative Study of Aryl O-, C-, and S-Mannopyranosides as Potential Adhesion Inhibitors toward Uropathogenic E. coli FimH.

ABSTRACT: A set of three mannopyranoside possessing identical 1,1'-biphenyl glycosidic pharmacophore but different aglyconic atoms were synthesized using either a palladium-catalyzed Heck cross coupling reaction or a metathesis reaction between their corresponding allylic glycoside derivatives. Their X-ray structures, together with their calculated 3D structures, showed strong indicators to explain the observed relative binding abilities against E. coli FimH as measured by a improved surface plasmon resonance (SPR) method. Amongst the O-, C-, and S-linked analogs, the C-linked analog showed the best ability to become a lead candidate as antagonist against uropathogenic E. coli with a Kd of 11.45 nM.

SUBMITTER: Mousavifar L

PROVIDER: S-EPMC6804135 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Comparative Study of Aryl O-, C-, and S-Mannopyranosides as Potential Adhesion Inhibitors toward Uropathogenic E. coli FimH.

Mousavifar Leila L Vergoten Gérard G Charron Guillaume G Roy René R

Molecules (Basel, Switzerland) 20191002 19

A set of three mannopyranoside possessing identical 1,1'-biphenyl glycosidic pharmacophore but different aglyconic atoms were synthesized using either a palladium-catalyzed Heck cross coupling reaction or a metathesis reaction between their corresponding allylic glycoside derivatives. Their X-ray structures, together with their calculated 3D structures, showed strong indicators to explain the observed relative binding abilities against E. coli FimH as measured by a improved surface plasmo ...[more]

PMID: 31581627

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Project description:Uropathogenic Escherichia coli express hairlike proteinaceous surface projections, known as chaperone-usher pathway (CUP) pili. Type 1 pili are CUP pili with well-established pathogenic properties. The FimH adhesin subunit of type 1 pili plays a key role in the pathogenesis of urinary tract infections (UTIs) as it mediates the adhesion of the bacteria to urothelial cells of the bladder. In this study, two breast cancer cell lines, MDA-MB-231 and MCF-7, were used to demonstrate the cytotoxic activities of type 1 piliated uropathogenic E. coli UTI89 on breast cancer cells in a type 1 pili and FimH-mediated manner. E. coli were grown in static and shaking conditions to induce or inhibit optimal type 1 pili biogenesis, respectively. Deletion constructs of UTI89 ΔfimH and a complemented strain (UTI89 ΔfimH/pfimH) were further utilized to genetically assess the effect of type 1 pili and FimH on cancer cell viability. After incubation with the different strains, cytotoxicity was measured using trypan blue exclusion assays. UTI89 grown statically caused significant cytotoxicity in both breast cancer cell lines whereas cytotoxicity was reduced when the cells were incubated with bacteria grown under shaking conditions. The incubation of both MDA-MB-231 and MCF-7 with UTI89 Δfim operon or ΔfimH showed a significant reduction in cytotoxicity exerted by the bacterial strains, revealing that type 1 pili expression was necessary for cytotoxicity. Complementing the ΔfimH strain with pfimH reversed the phenotype, leading to a significant increase in cytotoxicity. Incubating type 1 pili expressing bacteria with the competitive FimH inhibitor D-mannose before cancer cell treatment also led to a significant reduction in cytotoxicity on both MDA-MB-231 and MCF-7 cancer cells, compared to vehicle control or D-mannose alone, indicating the requirement for functional FimH for cytotoxicity. Overall, our results reveal that, as opposed to UTI89 lacking type 1 pili, type 1 piliated UTI89 causes significant cancer cell mortality in a FimH-mediated manner, that is decreased with D-mannose.

Dataset Information

Comparative Study of Aryl O-, C-, and S-Mannopyranosides as Potential Adhesion Inhibitors toward Uropathogenic E. coli FimH.

Publications

Comparative Study of Aryl <i>O</i>-, <i>C</i>-, and <i>S</i>-Mannopyranosides as Potential Adhesion Inhibitors toward Uropathogenic <i>E. coli</i> FimH.

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