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

Mousavifar, Leila; Vergoten, Gérard; Charron, Guillaume; Roy, René

doi:10.3390/molecules24193566

Cited by 8 publications

(19 citation statements)

References 52 publications

(91 reference statements)

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“…Para-substituted biphenyl derivatives were shown to be particularly appealing, owing to their numerous favorable binding interactions within the tyrosine gate. Thus, the structural and functional analyses of a series of O-, C-, and S-linked mannoside derivatives, incorporating the 1,1 -biphenyl pharmacophore and diverse aglycone atoms, demonstrated the suitability of these antagonists, establishing the possibility of further exploring these chemically modified mannosides [101,102]. Furthermore, it was shown that the biphenyl group linked to mannosides can be efficiently absorbed if orally administered [54,88].…”

Section: Fimh Antagonists Biochemical Characteristics and Bioavailabmentioning

confidence: 96%

“…It has been shown that O-and C-linked α-d-mannosides with hydrophobic and aryl substituents are potent E. coli FimH antagonists, having an affinity in the same range as that of nanomolar [101]. Indeed, the conformation and lipophilicity of aglycone moieties, their position with respect to the core sugar structure and the type of chemical group determine the RIP of antagonist molecules [61,80].…”

Section: Fimh Antagonists Biochemical Characteristics and Bioavailabmentioning

confidence: 99%

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FimH and Anti-Adhesive Therapeutics: A Disarming Strategy Against Uropathogens

et al. 2020

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Chaperone-usher fimbrial adhesins are powerful weapons against the uropathogens that allow the establishment of urinary tract infections (UTIs). As the antibiotic therapeutic strategy has become less effective in the treatment of uropathogen-related UTIs, the anti-adhesive molecules active against fimbrial adhesins, key determinants of urovirulence, are attractive alternatives. The best-characterized bacterial adhesin is FimH, produced by uropathogenic Escherichia coli (UPEC). Hence, a number of high-affinity mono- and polyvalent mannose-based FimH antagonists, characterized by different bioavailabilities, have been reported. Given that antagonist affinities are firmly associated with the functional heterogeneities of different FimH variants, several FimH inhibitors have been developed using ligand-drug discovery strategies to generate high-affinity molecules for successful anti-adhesion therapy. As clinical trials have shown d-mannose’s efficacy in UTIs prevention, it is supposed that mannosides could be a first-in-class strategy not only for UTIs, but also to combat other Gram-negative bacterial infections. Therefore, the current review discusses valuable and effective FimH anti-adhesive molecules active against UTIs, from design and synthesis to in vitro and in vivo evaluations.

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Section: Fimh Antagonists Biochemical Characteristics and Bioavailabmentioning

confidence: 96%

Section: Fimh Antagonists Biochemical Characteristics and Bioavailabmentioning

confidence: 99%

FimH and Anti-Adhesive Therapeutics: A Disarming Strategy Against Uropathogens

et al. 2020

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“…For this reason, molecules able to interfere with bacterial virulence mechanisms have been proposed to combat UPEC infections [20]. Accordingly, FimH antagonists, such as d-mannose and its derivatives, have emerged as anti-virulence therapeutic strategies for the treatment of UTIs [21][22][23][24][25][26][27]. d-mannose, a C-2 epimer of d-glucose, as well as d-mannose-analogs, prevent FimH-mediated bacterial adhesion through a competitive inhibition mechanism [18,21,22,24,28].…”

Section: Introductionmentioning

confidence: 99%

d-Mannose Treatment neither Affects Uropathogenic Escherichia coli Properties nor Induces Stable FimH Modifications

et al. 2020

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Urinary tract infections (UTIs) are mainly caused by uropathogenic Escherichia coli (UPEC). Acute and recurrent UTIs are commonly treated with antibiotics, the efficacy of which is limited by the emergence of antibiotic resistant strains. The natural sugar d-mannose is considered as an alternative to antibiotics due to its ability to mask the bacterial adhesin FimH, thereby preventing its binding to urothelial cells. Despite its extensive use, the possibility that d-mannose exerts “antibiotic-like” activity by altering bacterial growth and metabolism or selecting FimH variants has not been investigated yet. To this aim, main bacterial features of the prototype UPEC strain CFT073 treated with d-mannose were analyzed by standard microbiological methods. FimH functionality was analyzed by yeast agglutination and human bladder cell adhesion assays. Our results indicate that high d-mannose concentrations have no effect on bacterial growth and do not interfere with the activity of different antibiotics. d-mannose ranked as the least preferred carbon source to support bacterial metabolism and growth, in comparison with d-glucose, d-fructose, and l-arabinose. Since small glucose amounts are physiologically detectable in urine, we can conclude that the presence of d-mannose is irrelevant for bacterial metabolism. Moreover, d-mannose removal after long-term exposure did not alter FimH’s capacity to bind to mannosylated proteins. Overall, our data indicate that d-mannose is a good alternative in the prevention and treatment of UPEC-related UTIs.

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“…The substitution of biphenyl derivatives may provide additional advantages for the FimH antagonist molecule. The addition of 1,10-biphenyl pharmacophore and various aglycone atoms enhanced the alpha- d -mannose derivatives’ suitability as FimH inhibitors [ 59 , 60 ]. Further, glycomimetics based on mannose scaffolding has also been synthesized and widely studied for their aptitude as FimH antagonists [ 61 , 62 ].…”

Section: Resultsmentioning

confidence: 99%

Biocomputational Prediction Approach Targeting FimH by Natural SGLT2 Inhibitors: A Possible Way to Overcome the Uropathogenic Effect of SGLT2 Inhibitor Drugs

et al. 2021

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The Food and Drug Administration (FDA) approved a new class of anti-diabetic medication (a sodium–glucose co-transporter 2 (SGLT2) inhibitor) in 2013. However, SGLT2 inhibitor drugs are under evaluation due to their associative side effects, such as urinary tract and genital infection, urinary discomfort, diabetic ketosis, and kidney problems. Even clinicians have difficulty in recommending it to diabetic patients due to the increased probability of urinary tract infection. In our study, we selected natural SGLT2 inhibitors, namely acerogenin B, formononetin, (−)-kurarinone, (+)-pteryxin, and quinidine, to explore their potential against an emerging uropathogenic bacterial therapeutic target, i.e., FimH. FimH plays a critical role in the colonization of uropathogenic bacteria on the urinary tract surface. Thus, FimH antagonists show promising effects against uropathogenic bacterial strains via their targeting of FimH’s adherence mechanism with less chance of resistance. The molecular docking results showed that, among natural SGLT2 inhibitors, formononetin, (+)-pteryxin, and quinidine have a strong interaction with FimH proteins, with binding energy (∆G) and inhibition constant (ki) values of −5.65 kcal/mol and 71.95 µM, −5.50 kcal/mol and 92.97 µM, and −5.70 kcal/mol and 66.40 µM, respectively. These interactions were better than those of the positive control heptyl α-d-mannopyranoside and far better than those of the SGLT2 inhibitor drug canagliflozin. Furthermore, a 50 ns molecular dynamics simulation was conducted to optimize the interaction, and the resulting complexes were found to be stable. Physicochemical property assessments predicted little toxicity and good drug-likeness properties for these three compounds. Therefore, formononetin, (+)-pteryxin, and quinidine can be proposed as promising SGLT2 inhibitors drugs, with add-on FimH inhibition potential that might reduce the probability of uropathogenic side effects.

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

Cited by 8 publications

References 52 publications

FimH and Anti-Adhesive Therapeutics: A Disarming Strategy Against Uropathogens

FimH and Anti-Adhesive Therapeutics: A Disarming Strategy Against Uropathogens

d-Mannose Treatment neither Affects Uropathogenic Escherichia coli Properties nor Induces Stable FimH Modifications

Biocomputational Prediction Approach Targeting FimH by Natural SGLT2 Inhibitors: A Possible Way to Overcome the Uropathogenic Effect of SGLT2 Inhibitor Drugs

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