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

Abstract

<jats:p>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.</jats:p>

It’s Not Easy Being Green: A Narrative Review on the Microbiology, Virulence and Therapeutic Prospects of Multidrug-Resistant Pseudomonas aeruginosa

“…Additionally, it is questionable how long the new agents can manage the worsening resistance situation [146,157,[249][250][251][252][253][254]. With the daunting increase in antimicrobial resistance rates in all types of bacteria, one of the main aims of antimicrobial research is the exploration for new approaches past conventional antibiotics, such as bacteriophages, antimicrobial peptides with diverse structures and mechanisms of action, virulence inhibitors, siderophores, compounds from natural origins (like essential oils), and other adjuvants (e.g., efflux pump inhibitors, monoclonal antibodies) (Table 3) [118,[255][256][257][258][259][260][261][262][263][264][265][266][267][268][269][270]. It is possible that in the next couple of decades, these agents will play a major role in the management of serious bacterial infections caused by P. aeruginosa and other pathogens of critical importance.…”

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

“…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 ]. Besides synthetic compounds, natural substances, like cranberry and its derivatives (such as myricetin, proanthocyanidin (PAC)-standardized cranberry extract, and polyphenol metabolites extracted from PAC), have anti-adhesive effects on uropathogenic E. coli [ 63 ].…”

CT and MRI in Urinary Tract Infections: A Spectrum of Different Imaging Findings

“…UTIs can be caused by many types of micro-organisms, including Gram-positive bacteria, Gram-negative bacteria and certain fungi. Uropathogenic Escherichia coli (UPEC) is the commonest causative organism for both complicated and uncomplicated UTIs [ 5 , 6 , 7 , 8 ]. Undetected and untreated acute pyelonephritis may lead to renal hypertension, renal scarring, and even renal failure [ 9 ].…”