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.

Keywords: FimH; adhesins; affinity; antagonists; mannose-binding lectin; urinary tract infection; uropathogenic Escherichia coli; uropathogenic Klebsiella pneumoniae; uropathogenic Proteus mirabilis.

Figure 1

The structure of FimH co-crystallized with FimC. The FimH_PD, FimH_LD, Tyrosine Gate (Tyr137, Ile52 and Tyr48), molecule of mannose and FimC is shown (1KLF PDB file) [62]. FimC is a chaperone protein that does not belong to the mature fimbria.

Figure 2

The structure of the tyrosine gate of FimH_LD MBP in UPEC (Tyr137, Ile52 and Tyr48). The ligand is α-D-mannoside O-linked to a propynyl pyridine (4AV4 PDB file) [64].

Figure 3

The Tyr48Ala mutation within the relaxed Tyrosine Gate of MBP in FimH_LD from UPEC. The linkage of Heptyl-α-D-mannopyrannoside with mutated Tyrosine Gate is shown. The stacking pattern between Tyr137, Ile52, Ala48 and Heptyl-α-D-mannopyrannoside is shown (4CA4 PDB file) [65].

Figure 4

The successful linkage between Tyrosine Gate (Fim_LD MBP) and the bioisostere of 3′-chloro-4′-(α-d-mannopyranosyloxy)-biphenyl-4-carbonitrile (4CST PDB file) [47].