Computational Study of Antibiotic Resistance Mechanisms in Diarrheal Pathogens and Identification of Potential Drug Targets and Vaccine Candidates

Abstract

Diarrheal diseases are the second leading cause of children deaths under age five worldwide. Diarrhea is caused by a wide variety of organism including bacteria viruses parasites and helminthes. Due to emergence of clinically significant cases of antibiotic resistance in diarrheal pathogens the problem of antibiotic resistance surfaced as a global health problem. Single Nucleotide Polymorphisms have a vast potential to be utilized as molecular diagnostics for gene-disease or pharmacogenomics association studies linking genotype to phenotype. In this study we first developed a database DBDiaSNP which contains information about 946 clinically significant mutations and 326 resistance genes compiled for pathogens such as DEC DiarrheagenicE. coli Salmonella spp. Campylobacter spp. Shigella spp. C.difficile E. histolytica V. cholerae and viruses. For future translational research involving integrative biology and global health the database offers veritable potentials particularly for worldwide monitoring. To understand the molecular events underlying the mechanism of drug resistance fully atomistic explicit-water solvated molecular dynamics simulations of wild-type and mutant forms of gyrA in EnterotoxigenicE. coli ETEC and C. jejunicomplexed with ciprofloxacin were performed. This study offers insights into molecular events central to the gyrA-ciprofloxacin interaction consequently would aid in design of more potent antibacterial agents with high ligand efficacy for treating drug resistant bacterial infections. We have employed a range of omics and systems biology approaches to investigate the entire genome/ proteome/ metabolome of pathogens viz. ETEC C. jejuni and S. typhimurium to instigate the search for potential therapeutic drug targets and vaccine candidates. Majority of the metabolites identified as potential drug targets are involved in cell wall synthesis fatty acid synthesis and bacterial secretion systems which are crucial for bacterial growth and viability. newline