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Identification of potential drug targets by subtractive genome analysis of
Escherichia coli O157:H7: an in silico approach
#MMPMID26677339
Mondal SI
; Ferdous S
; Jewel NA
; Akter A
; Mahmud Z
; Islam MM
; Afrin T
; Karim N
Adv Appl Bioinform Chem
2015[]; 8
(?): 49-63
PMID26677339
show ga
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 bio-informatic 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-sulfon-amide 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.
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