Lead Optimization Studies on FimH Antagonists: Discovery of Potent and Orally Bioavailable Ortho-Substituted Biphenyl Mannosides

Abstract

Herein, we describe the X-ray structure-based design and optimization of biaryl mannoside FimH inhibitors. Diverse modifications to the biaryl ring to improve druglike physical and pharmacokinetic properties of mannosides were assessed for FimH binding affinity based on their effects on hemagglutination and biofilm formation along with direct FimH binding assays. Substitution on the mannoside phenyl ring ortho to the glycosidic bond results in large potency enhancements several-fold higher than those of corresponding unsubstituted matched pairs and can be rationalized from increased hydrophobic interactions with the FimH hydrophobic ridge (Ile13) or “tyrosine gate” (Tyr137 and Tyr48) also lined by Ile52. The lead mannosides have increased metabolic stability and oral bioavailability as determined from in vitro PAMPA predictive model of cellular permeability and in vivo pharmacokinetic studies in mice, thereby representing advanced preclinical candidates with promising potential as novel therapeutics for the clinical treatment and prevention of recurring urinary tract infections.

Combinatorial Small-Molecule Therapy Prevents Uropathogenic Escherichia coli Catheter-Associated Urinary Tract Infections in Mice

“…Methyl mannose exhibits poor bioavailability (1), whereas mannoside compounds 6, 8, and 10 have recently been shown to be orally bioavailable (8,19) and potent therapeutics in the treatment and prevention of acute and chronic UPEC infections (8). Mannoside 6 is ϳ1,000-fold more active in inhibiting FimH than are methyl mannose and heptyl mannose (which is a more potent inhibitor of FimH than methyl mannose) both in vitro and in vivo (8,15,20,61).…”

“…Mannosides such as mannoside 6 (20) have been shown to be orally bioavailable in a murine model (8,19). Oral administration is able to efficaciously treat chronic UTI via a potent fast-acting mechanism (8) that is capable of potentiating the efficacy of trimethoprim-sulfamethoxazole (TMP-SMZ) (8).…”

Anti-virulence Strategies to Target Bacterial Infections

“…Biphenyl mannosides were shown to be 200,000 fold more potent than the originally tested monovalent mannose. The substances are orally available and demonstrate an overall low toxicity (Han et al 2012;Hartmann et al 2012). Additionally, mouse models indicate that biphenyl mannosides decrease colonization levels significantly (Klein et al 2010).…”

Glycoconjugates and Glycomimetics as Microbial Anti-Adhesives

“…Prevention and treatment of urinary tract infection by UPEC requires orally active FimH antagonists, absorbed in the intestine and renally excreted, with finely tuned pharmacokinetic properties, so as to achieve an optimal balance between affinity and duration of the therapeutic effect in the bladder. This is typically pursued with monovalent aryl mannosides [13][14][15][16][17] targeted to the FimH binding site by their mannose component and carrying extended aromatic aglycones that establish high affinity interaction with the tyrosine gate (3-5, Figure 1a). Extensive medicinal chemistry programs are under way, including the use of prodrugs and bioisosters to achieve optimal pharmacological profile of these structures [18].…”

“…The biochemical and structural data that have been accumulating on sugar-protein interactions, and the current ability to decipher the sequence and function of cell-associated glycans, will surely offer in the near future the possibility of developing novel tools to interfere in the infection process using materials that mimic the natural presentation of adhesion oligosaccharides. [8], heptyl α-D-mannoside (α-D-HM) 2 [9], 3 [13], 4 [15] and 5 [17] for antiadhesion therapy of urinary tract infections; FimH antagonist 6 [32,33] was developed for antiadhesion of AIEC to intestinal cells; b) Surface functionalization of small NDs 5 by Diels-Alder reaction of an in situ generated o-quinodimethide [27]. The sugar 10 is grafted using a thiol-ene reaction [34]; c)…”