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

Abstract

Blocking the adherence of bacteria to cells is an attractive complementary approach to current antibiotic treatments, which are faced with increasing resistance. This strategy has been particularly studied in the context of urinary tract infections (UTIs), in which the adhesion of pathogenic Escherichia coli strains to uroepithelial cells is prevented by blocking the FimH adhesin expressed at the tips of bacteria organelles called fimbriae. Recently, we extended the antiadhesive concept, showing that potent FimH antagonists can block the attachment of adherent-invasive E. coli (AIEC) colonizing the intestinal mucosa of patients with Crohn's disease (CD). In this work, we designed a small library of analogues of heptyl mannoside (HM), a previously identified nanomolar FimH inhibitor, but one that displays poor antiadhesive effects in vivo. The anomeric oxygen atom was replaced by a sulfur or a methylene group to prevent hydrolysis by intestinal glycosidases, and chemical groups were attached at the end of the alkyl tail. Importantly, a lead compound was shown to reduce AIEC levels in the feces and in the colonic and ileal mucosa after oral administration (10 mg kg(-1) ) in a transgenic mouse model of CD. The compound showed a low bioavailability, preferable in this instance, thus suggesting the possibility of setting up an innovative antiadhesive therapy, based on the water-soluble and non-cytotoxic FimH antagonists developed here, for the CD subpopulation in which AIEC plays a key role.

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

“…A high inoculum of >10 9 CFU of the AIEC strain LF82 is given orally and mice are monitored for weight loss and fecal AIEC titers, and ileal tissues analyzed for bacterial burdens, AIEC colonization, and histopathology [68]. To test the efficacy of oral FimH antagonists in preventing Crohn's-like clinical signs and pathology in this mouse CEABAC10 model, mice were treated with 10 mg/kg of candidate compounds at 2 and 18 hpi and monitored over 3-4 days for weight loss, fecal and/or tissue titers, and ileal tissue histopathology and soluble mediators of inflammation [22, 69]. The FimH antagonists tested in these publications all showed efficacy in preventing Crohn's-like clinical signs and pathology, demonstrating the proof of concept that FimH antagonists could potentially be used to treat Crohn's symptoms in patients.…”

“…In another series targeting AIEC bacteria in CD, Gouin[22] designed a sulfur and carbon-linked heptyl O -mannoside (HM) derivatives (Fig. 7).…”

“…In these cases, chronic inflammation of the ileal epithelium leads to over-expression of the highly-mannosylated, carcinoembryonic antigen-related cell adhesin molecule 6 (CEACAM6), which FimH can then bind to, enabling AIEC to adhere to and invade the gut mucosa. Current results have been promising, clearly demonstrating the ability of FimH antagonists to both decrease the AIEC population and mitigate the inflammatory response [22]. …”

Growth Control of Adherent-Invasive Escherichia coli (AIEC) by the Predator Bacteria Bdellovibrio bacteriovorus: A New Therapeutic Approach for Crohn’s Disease Patients

“…To date, several strategies focused on AIEC growth control and reduction on intestinal mucosae are under study, such as the use of antibiotics, the attempt to block AIEC's adhesion ability by preventing the interaction between FimH and CEACAM6 [18,19], and the attempt to block AIEC's cell-invasion ability using the Gp96 chaperone or the OmpA trans-membrane proteins as targets [20,[42][43][44].…”

Inhibition of adherence of the yeast Candida albicans to buccal epithelial cells by synthetic aromatic glycoconjugates

“…There are several examples in which the anti-adherence approach has been exploited successfully to design inhibitors of microbial adherence [6]. Some of these include glycoclusters capable of preventing lung infection caused by Pseudomonas aeruginosa [7] and glycoconjugates used in the treatment of conditions caused by pathogenic strains of Escherichia coli, such as Crohn's disease [8] and urinary tract infections [9,10]. The lectins involved in the adherence processes in these reports (Lec A and Lec B from P. auroginosa and Fim H from E. coli, respectively) have been extensively studied and detailed knowledge of their structure and binding specificities is available.…”