Identification of Potential Drug Targets in Helicobacter pylori Using In Silico Subtractive Proteomics Approaches and Their Possible Inhibition through Drug Repurposing.

Kareem A Ibrahim,Omneya M Helmy,Mohammed A Ramadan,Mona T Kashef,Tharwat R Elkhamissy

doi:10.3390/pathogens9090747

Kareem A Ibrahim, Omneya M Helmy + Show 3 more

Open Access

https://doi.org/10.3390/pathogens9090747

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Abstract

The class 1 carcinogen, Helicobacter pylori, is one of the World Health Organization’s high priority pathogens for antimicrobial development. We used three subtractive proteomics approaches using protein pools retrieved from: chokepoint reactions in the BIOCYC database, the Kyoto Encyclopedia of Genes and Genomes, and the database of essential genes (DEG), to find putative drug targets and their inhibition by drug repurposing. The subtractive channels included non-homology to human proteome, essentiality analysis, sub-cellular localization prediction, conservation, lack of similarity to gut flora, druggability, and broad-spectrum activity. The minimum inhibitory concentration (MIC) of three selected ligands was determined to confirm anti-helicobacter activity. Seventeen protein targets were retrieved. They are involved in motility, cell wall biosynthesis, processing of environmental and genetic information, and synthesis and metabolism of secondary metabolites, amino acids, vitamins, and cofactors. The DEG protein pool approach was superior, as it retrieved all drug targets identified by the other two approaches. Binding ligands (n = 42) were mostly small non-antibiotic compounds. Citric, dipicolinic, and pyrophosphoric acid inhibited H. pylori at an MIC of 1.5–2.5 mg/mL. In conclusion, we identified potential drug targets in H. pylori, and repurposed their binding ligands as possible anti-helicobacter agents, saving time and effort required for the development of new antimicrobial compounds.

Highlights

Helicobacter pylori is one of the most common infectious agents in the world, colonizing more than half of the global population, especially in developing countries where over 80% of their population are infected [1]
Three different in silico approaches were used to search for promising drug targets in targets pylori, all of which used almost the same tools, with the same parameters, but in a different order
Chokepoint reactions of H. pylori ATCC 43504 were retrieved from the BIOCYC collection database [79], available at http://biocyc.org/chokepoint-form.shtml, with the following criteria: exclusion of reactions found in humans, exclusion of reactions catalyzed by more than one enzyme, 4.1.1

Summary

Introduction

Helicobacter pylori is one of the most common infectious agents in the world, colonizing more than half of the global population, especially in developing countries where over 80% of their population are infected [1]. H. pylori has been identified, since 1994, as a class-1 carcinogen [3]; it is the primary identified cause of gastric cancer, which is the second most common cause of cancer-related deaths worldwide [4]. In H. pylori infections, is the biggest issue in treatment failures alongside resistance development to the antimicrobial agents [6]. This is further complicated by the risk of re-infection, especially in areas with high H. pylori infection prevalence [7]

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