Urinary tract infections (UTIs) by uropathogenic Escherichia coli (UPEC) belong to the most common bacterial infections worldwide. Person that once is affected with infection will most likely experience recurrent infection. The current treatment generally involves antibiotics. Due to their frequent and non-critical use lead to bacterial resistance. The need to develop non-antibiotic strategies is huge. A new alternative approach in the treatment of bacterial infections is the use of antiadhesives.
Uropathogenic E.coli express fimbriae type 1, organelles which protrude from the bacterial surface, at the tip of which is FimH lectin. Lectin FimH has a high connective affinity towards α-D-mannoside of a host cell, because it contains CRD, the mannose-specific carbohydrate recognition domain. Adhesion of the pathogen to host cells represents one of the first steps in causing infection. Virulent lectins can be blocked with compounds, called FimH antagonists that represent naturally occurring carbohydrates on cells. Antagonists bind to the FimH lectin receptor site. Consequently, because of FimH saturation, bacteria E.coli cannot be attached to the urothelium cells. In this way, bacterial adhesion is prevented, and the infection is consequently formed. The new UTI treatment and prevention strategy are called anti-adhesive therapy.
By using the method of molecular docking, with Glide program, part of the Schrödinger Suite 2018 software package, antagonists were linked into the receptor region of lectin FimH. The basic framework of all studied antagonists contained α-D-mannose. All hydroxide groups, except the anomeric one, form a favorable network of hydrogen bonds in the receptor site. I used the anomeric center of α-D-mannose to attach the aglycone moiety of the antagonists, thereby improving the binding affinity. I divided the 70 studied antagonists into three groups and examined each one using the method of molecular docking. The binding strength provided by the Glide XP evaluation function, the logP parameter and previously experimentally determined IC50 values of antagonists are some of the information of what antagonists might represent the new active substances for infection. The UL-AAG-13 antagonist could demonstrate the great potential for effective treatment of urinary tract infections.
The method of molecular docking is an important tool in biomedical research and for discovery of novel drugs. The method helps to select in the base of a million ligands only a few potentials that would fit the criteria for further research. Of the 70 studied antagonists, at least 4 selected could represent potential new active substances and prevent or at least, alleviate urinary tract infections. The increasing use of antiadhesives would slowly eliminate the use of antibiotics in the treatment of infection.
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