Novel Drug Targets for Food-Borne PathogenCampylobacter jejuni: An Integrated Subtractive Genomics and Comparative Metabolic Pathway Study

Abstract

Campylobacters are a major global health burden and a cause of food-borne diarrheal illness and economic loss worldwide. In developing countries, Campylobacter infections are frequent in children under age two and may be associated with mortality. In developed countries, they are a common cause of bacterial diarrhea in early adulthood. In the United States, antibiotic resistance against Campylobacter is notably increased from 13% in 1997 to nearly 25% in 2011. Novel drug targets are urgently needed but remain a daunting task to accomplish. We suggest that omics-guided drug discovery is timely and worth considering in this context. The present study employed an integrated subtractive genomics and comparative metabolic pathway analysis approach. We identified 16 unique pathways from Campylobacter when compared against H. sapiens with 326 non-redundant proteins; 115 of these were found to be essential in the Database of Essential Genes. Sixty-six proteins among these were non-homologous to the human proteome. Six membrane proteins, of which four are transporters, have been proposed as potential vaccine candidates. Screening of 66 essential non-homologous proteins against DrugBank resulted in identification of 34 proteins with drug-ability potential, many of which play critical roles in bacterial growth and survival. Out of these, eight proteins had approved drug targets available in DrugBank, the majority serving crucial roles in cell wall synthesis and energy metabolism and therefore having the potential to be utilized as drug targets. We conclude by underscoring that screening against these proteins with inhibitors may aid in future discovery of novel therapeutics against campylobacteriosis in ways that will be pathogen specific, and thus have minimal toxic effect on host. Omics-guided drug discovery and bioinformatics analyses offer the broad potential for veritable advances in global health relevant novel therapeutics.

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

“…Both quinic and shikimic organic acid exert an inhibitory effect on Staphylococcus aureus [ 76 ]; we detected some of their derivatives (3-dehydroquinic acid; 2,3-anhydro-quinic acid; 3-hydroxyimino quinic acid; 2-anhydro-3-fluoro-quinic acid; 3-dehydroshikimate) as AroQ binding ligands. Most of the AroE, AroQ, CheY, DapB, Ddl, LpxA, and PanD detected binding ligands were previously reported, in a similar in silico study, to bind to the same targets in Campylobacter jejuni [ 77 ].…”

In Silico Screening and Analysis of Broad-Spectrum Molecular Targets and Lead Compounds for Diarrhea Therapy

“…Previous in silico studies have reported several potential drug targets through inclusive stepwise subtractive process of comparative genomic analysis of E. coli O157:H7 (a typical EHEC) and C. jejuni . 6,18,36…”

“…Previous in silico studies have reported several potential drug targets through inclusive stepwise subtractive process of comparative genomic analysis of E. coli O157:H7 (a typical EHEC) and C. jejuni. 6,18,36 About 60 antidiarrheal compounds were obtained from available literature ( Table 2). Twenty-one of these compounds were found to possess relevant functional characteristics based on the nature of targets that were predicted for 5 reference ligands used in this study, as well as reported function related to diarrheal and absence of cases of liver injury or other acute toxicity.…”

“…The reference ligands used in the study were cycloserine (DB00260), fosfomycin (DB00828), cefmetazole (DB00274), cefazolin (DB01327), and azithromycin. 4,18 Available structures of most of the compounds were obtained from the PubChem Compound Database in canonical SMILES format as well as Pathogen Box activity biological data structure and SMILES, 19 while unavailable structures were constructed using ChemSketch interface of ACDLabs (Freeware) 2015, version 2.5. The ligand structures generated were subjected to 3-dimensional (3D) optimization and saved in SMILES format.…”

Questing functions and structures of hypothetical proteins from Campylobacter jejuni: a computer-aided approach

“…In developing countries, infections with Campylobacter are common in children under 2 years of age and found to be associated with increased incidence of diarrheal diseases as well as mortality [1,2]. In industrialized nations, Campylobacter is the cause of diarrhea during early years of adulthood [3]. Campylobacter infections are mostly acquired through consumption of contaminated water and food in resource-poor environment [4].…”