Inhibition profiles of mono- and polyvalent FimH antagonists against 10 different Escherichia coli strains

Abstract

Mono- and polyvalent ligands with strong affinities for the mannose-binding adhesin FimH were synthesised, and their anti-adhesive properties against ten E. coli strains were compared in two cell-based assays. The compounds were assessed against the non-pathogenic E. coli K12 and nine strains isolated by coproculture or from patients with osteoarticular infections (OIs), Crohn's disease (CD) and urinary tract infections (UTIs). The results showed that the compounds could inhibit the whole set of bacterial strains but with marked differences in terms of effective concentrations. The relative inhibitory potency of the monovalent compounds was also conserved for the ten strains and in the two assays. These results clearly suggest that a potent monovalent anti-adhesive assessed on a single E. coli strain will probably be effective on a broad range of strains and may treat diverse E. coli infections (OIs, CD and UTIs). In contrast, the polyvalent compounds showed a significant strain-dependancy in preventing E. coli attachment to intestinal cells. The multivalent antiadhesive effect may therefore vary depending on the E. coli strain tested.

Physiochemical Tuning of Potent Escherichia coli Anti‐Adhesives by Microencapsulation and Methylene Homologation

“…Such a stabilizing interaction has recently been observed by Janetka and co‐workers with biphenyl‐ C ‐mannosides bearing anomeric hydroxyalkyl groups . The compounds included in our recent study also lacked the second thiazole and pyrazine ring of 2 , the most potent FimH antagonist of the series, which showed outstanding in vitro anti‐adhesive effects . In this work, we developed a new series of TazMans based on a co‐crystal structure of 2 –FimH (Figure C).…”

“…Prior to starting our investigation, we wanted to gain more insight into the generally high anti‐adhesive potency of the TazMan series and particularly of the best compound 2 which is ∼100‐fold more potent than the reference compound HM, and 50 to 100‐fold more potent than 1 . Co‐crystals were obtained using the vapor diffusion method similar to a previously published protocol .…”

“…The thiazolylaminomannosides (TazMans) family (i.e., compounds 1 and 2 , Figure ), recently developed in our research group, are highly potent E. coli anti‐adhesives in eukaryotic cells, preventing the adhesion of a broad range of E. coli strains isolated from patients with UTIs, Crohn's disease or osteoarticular infections . However, this first generation suffered from an anomerization of the heteroarylamino groups at low pH from the active α to the inactive β form.…”

The Antiadhesive Strategy in Crohn′s Disease: Orally Active Mannosides to Decolonize Pathogenic Escherichia coli from the Gut

“…These results are significant, because they confirm the feasibility of the antiadhesive concept in a curative treatment for CD. We have recently shown the broad antiadhesive potential of FimH antagonists, so the compound might also be effective against other E. coli infections.…”

Rational design strategies for FimH antagonists: new drugs on the horizon for urinary tract infection and Crohn’s disease

“…While this focus has largely been replaced by the rational design of orally bioavailable lower molecular monomeric mannosides, several multivalent mannoside inhibitors have been reported, including glycodendrimers and neoglycoproteins [107-108], CD-based HMs [69, 109-114], glycoclusters [115-116], and others [117-120]. While these have been extensively reviewed previously [121-122], we present select examples of smaller, di-and tri-valent mannosides in the following discussion.…”