Advances and Applications in Bioinformatics and Chemistry (Dec 2015)
Identification of potential drug targets by subtractive genome analysis of Escherichia coli O157:H7: an in silico approach
Abstract
Shakhinur Islam Mondal,1,6,* Sabiha Ferdous,1,* Nurnabi Azad Jewel,1 Arzuba Akter,2,6 Zabed Mahmud,1 Md Muzahidul Islam,1 Tanzila Afrin,3 Nurul Karim4,5 1Genetic Engineering and Biotechnology Department, Shahjalal University of Science and Technology, Sylhet, Bangladesh; 2Biochemistry and Molecular Biology Department, Shahjalal University of Science and Technology, Sylhet, Bangladesh; 3Department of Pharmacy, East West University, Aftabnagar, Bangladesh; 4Biochemistry and Molecular Biology Department, Jahangirnagar University, Savar, Bangladesh; 5Division of Parasitology, 6Division of Microbiology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan *These authors contributed equally to this work Abstract: Bacterial enteric infections resulting in diarrhea, dysentery, or enteric fever constitute a huge public health problem, with more than a billion episodes of disease annually in developing and developed countries. In this study, the deadly agent of hemorrhagic diarrhea and hemolytic uremic syndrome, Escherichia coli O157:H7 was investigated with extensive computational approaches aimed at identifying novel and broad-spectrum antibiotic targets. A systematic in silico workflow consisting of comparative genomics, metabolic pathways analysis, and additional drug prioritizing parameters was used to identify novel drug targets that were essential for the pathogen’s survival but absent in its human host. Comparative genomic analysis of Kyoto Encyclopedia of Genes and Genomes annotated metabolic pathways identified 350 putative target proteins in E. coli O157:H7 which showed no similarity to human proteins. Further bioinformatic approaches including prediction of subcellular localization, calculation of molecular weight, and web-based investigation of 3D structural characteristics greatly aided in filtering the potential drug targets from 350 to 120. Ultimately, 44 non-homologous essential proteins of E. coli O157:H7 were prioritized and proved to have the eligibility to become novel broad-spectrum antibiotic targets and DNA polymerase III alpha (dnaE) was the top-ranked among these targets. Moreover, druggability of each of the identified drug targets was evaluated by the DrugBank database. In addition, 3D structure of the dnaE was modeled and explored further for in silico docking with ligands having potential druggability. Finally, we confirmed that the compounds N-coeleneterazine and N-(1,4-dihydro-5H-tetrazol-5-ylidene)-9-oxo-9H-xanthene-2-sulfonamide were the most suitable ligands of dnaE and hence proposed as the potential inhibitors of this target protein. The results of this study could facilitate the discovery and release of new and effective drugs against E. coli O157:H7 and other deadly human bacterial pathogens. Keywords: E. coli O157:H7, KEGG metabolic pathways, novel and broad-spectrum antibiotic targets, DNA polymerase III alpha, homology modeling
