Escherichia coli bacteria, among other pathogenic bacteria, are responsible for a large variety of human diseases, including persistent urinary tract and intestinal infections. Their adhesion to the host cell wall is promoted by the binding of FimH located at the tip of the bacterial fimbriae to highly mannosylated cell surface receptors. Currently, antibiotics are still the standard treatment for E. coli infections; however, their long-term use promotes the development of microbial resistance, leading to recurrent infections and thus accounting for significant morbidity. As FimH-targeting drugs do not interfere with the bacterial metabolism and they have neither a bacteriostatic nor a bacteriolytic effect, they are unlikely to induce bacterial resistance. The reversible FimH-dependent attachment of E. coli is a necessity for the bacterial infection and colonization. The inhibition of this process could thus present an attractive alternative route to common antibiotic treatment of E. coli mediated diseases. To develop such inhibitors, the molecular recognition between FimH and its human receptors has to be better understood.
The FimH-Mech project intended to decipher the molecular mechanism that determines the pathogenicity of different E. coli strains, by the complex formation with one of its target receptors, namely the carcinoembryonic antigen-related cell adhesion molecule 6 or CEACAM6 in short. The biochemical nature and composition of the glycan attached to CEACAM6 was also investigated. Therefore, the binding affinities of glycans of growing complexity to FimH have been determined. To perform this study, a large variety of state-of-the-art computational and theoretical techniques have been applied, inspired by and complemented with experimental data measured in the host institute. Molecular modelling, molecular dynamics and free energy calculations have been combined to gain an understanding of the molecular action of bacterial adhesins and more specifically to decipher the glycan code for FimH lectin binding. The project’s results will allow the future development of more effective inhibitors and mark a milestone in the design of novel, promising non-antibiotic drugs to tackle harmful adhesive bacteria.
