D-Mannoside FimH Inhibitors as Non-Antibiotic Alternatives for Uropathogenic Escherichia coli.

Alfredo Montes-Robledo,Johan Fabian Galindo,Rosa Baldiris-Avila

doi:10.3390/antibiotics10091072

Abstract

FimH is a type I fimbria of uropathogenic Escherichia coli (UPEC), recognized for its ability to adhere and infect epithelial urinary tissue. Due to its role in the virulence of UPEC, several therapeutic strategies have focused on the study of FimH, including vaccines, mannosides, and molecules that inhibit their assembly. This work has focused on the ability of a set of monosubstituted and disubstituted phenyl mannosides to inhibit FimH. To determine the 3D structure of FimH for our in silico studies, we obtained fifteen sequences by PCR amplification of the fimH gene from 102 UPEC isolates. The fimH sequences in BLAST had a high homology (97–100%) to our UPEC fimH sequences. A search for the three-dimensional crystallographic structure of FimH proteins in the PDB server showed that proteins 4X5P and 4XO9 were found in 10 of the 15 isolates, presenting a 67% influx among our UPEC isolates. We focused on these two proteins to study the stability, free energy, and the interactions with different mannoside ligands. We found that the interactions with the residues of aspartic acid (ASP 54) and glutamine (GLN 133) were significant to the binding stability. The ligands assessed demonstrated high binding affinity and stability with the lectin domain of FimH proteins during the molecular dynamic simulations, based on MM-PBSA analysis. Therefore, our results suggest the potential utility of phenyl mannoside derivatives as FimH inhibitors to mitigate urinary tract infections produced by UPEC; thus, decreasing colonization, disease burden, and the costs of medical care.

Highlights

Urinary tract infections (UTIs) are one of the main causes of visits to health centers around the world, with uropathogenic Escherichia coli (UPEC) being the main bacterial agent associated with UTIs [1]
In Colombia, there are few studies showing the characteristics of UPEC strains and the possible FimH proteins where these bacterial strains are present; the objectives of the present work are: (i) to identify and characterize strains of UPEC through phylogenetic analysis, different virulence factors, and antibiotic resistance genes, (ii) to sequence the fimH gene and to select the protein structures from the Protein Data Bank (PDB) for further in silico studies, (iii) to perform Molecular Docking and Molecular Dynamics (MD) simulations with a set of inhibitory molecules of fimbriae type 1 (FimH), and (iv) to complete an atomic characterization of the receptor–ligand type interactions, identifying possible inhibitor candidates with the lowest free energy interaction
The phylogroup assignment of the UPEC strains collected for this study revealed that phylogroups D and B2 were the most prevalent and were associated with diseases outside the gastrointestinal tract

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Urinary tract infections (UTIs) are one of the main causes of visits to health centers around the world, with uropathogenic Escherichia coli (UPEC) being the main bacterial agent associated with UTIs [1]. UTIs can be transmitted through the community (~90%) as well as hospitals (~50%), and are associated with high rates of morbidity [2]. UPEC strains can colonize urinary tissue and cause pathogenesis through diverse virulence factors, which are present in the chromosome or in mobile extrachromosomal material, such as plasmids [3]

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Conclusion