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

ABSTRACT: 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.

SUBMITTER: Sarshar M

PROVIDER: S-EPMC7400442 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Sarshar Meysam M Behzadi Payam P Ambrosi Cecilia C Zagaglia Carlo C Palamara Anna Teresa AT Scribano Daniela D

Antibiotics (Basel, Switzerland) 20200710 7

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 <i>Escherichia coli</i> (UPEC). Hence, a nu ...[more]

PMID: 32664222

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Project description:Objective:Considering the emergence of biofilm-associated pathogens with multidrug resistance, the objective(s) of the present study was to evaluate the anti-virulence property of Syzygium aromaticum extracts/fractions against 2 multidrug-resistant catheter isolates. Materials and Methods:Pulverized clove buds were subjected to bioactivity-guided isolation to identify the bioactive extract/fraction(s) with significant anti-virulence property. The clove bud powder was subjected to Soxhlet extraction and all these extracts were investigated in terms of anti-virulent efficacy using initial readout assays. Bioassay-guided partial purification was performed through column and size exclusion chromatography. Detailed testing of the anti-virulence and anti-biofilm activity of sub-minimum inhibitory concentration (sub-MIC) levels of the active fraction, was performed besides the cytotoxicity profiling in RAW 264.7 cells. Results:Gas chromatography-mass spectrometry (GC-MS) analysis of the clove bioactive fraction-2 (CBF-2), done after the bioassay-guided fractionation, revealed eugenol as the major bioactive ingredient present in CBF-2. Reduced mRNA levels of virulence factor genes after CBF-2 (700 ?g/ml) treatment correlated well with the respective phenotypic assays (p<0.001). Similarly, CBF-2 (700 ?g/ml) treatment exhibited significantly low mRNA levels of quorum sensing (QS) receptor genes compared to their cognate synthase genes (p<0.001). Crystal violet staining and scanning electron micrographs of CBF-2-treated biofilms showed lesser macrocolonies with remarkably simplified architecture. Cytotoxic evaluation of CBF-2 suggested a minute reduction in viability even at the highest tested concentration (1600 ?g/ml, p<0.05). Conclusion:The present study indicated that eugenol-rich CBF-2 has potent anti-virulence and anti-biofilm activity against urinary catheter isolates and can be regarded as an alternative for treatment of catheter-associated urinary tract infections.

Project description:BACKGROUND:Antibiotic resistance represents a serious global health threat to public health, so infections such as pneumonia and urinary tract infection (UTI) are becoming harder to treat. Therefore, it is necessary to develop an action plan to restrain the problem of antibiotic resistance. One approach in UTI control could be the use of lactobacilli because these indigenous inhabitants in human intestine have been found to play an important role in protecting the host from various infections. OBJECTIVES:We sought to check the efficacy of locally isolated Lactobacillus species to eradicate antibiotic-resistant pathogenic bacteria causing UTI. MATERIALS AND METHODS:Lactic acid bacteria isolated from spoiled fruits and vegetables and grown in MRS medium were screened against multi-drug-resistant Candida albicans, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, and Enterococcus fecalis. RESULTS:Fifty-four lactic acid bacteria were isolated from spoiled fruits and vegetables, of which 11 Gram-positive and catalase-negative Lactobacillus isolates were identified by carbohydrate assimilation profiles as Lactobacillus acidophilus, L. paracasei, L. delbrueckii, L. casei, L. helveticus, L. brevis, L. salivarius, L. fermentum, L. rhamnosus, L. animalis, and L. plantarum. The latter organism had the highest abundance of all the samples, so its isolates were also verified through 16S rRNA gene sequencing. The isolated Lactobacilli were screened against multi-drug-resistant uropathogens, viz. C. albicans, P. aeruginosa, K. pneumoniae, E. fecalis, and E. coli. The growth inhibition zone (GIZ) was over 10 mm against all the uropathogenic test organisms, where L. fermentum and L. plantarum strains demonstrated remarkable inhibitory activities against E. coli and E. faecalis, with a GIZ up to 28 mm. The susceptibility test to 16 antibiotics showed multidrug resistance (3 to 5 antibiotics) among all the tested uropathogens. CONCLUSIONS:The obtained results revealed that all the Lactobacillus isolates displayed antimicrobial activity against 6 out of 7 antibiotic-resistant uropathogens, indicating that these bacteria could represent a good ecological plan for the control and prevention of UTI.

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

Publications

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

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