Identification of the Plausible Drug Target via Network/Genome Analysis and Its Molecular Interaction Studies Against Multidrug Resistance Bacterial Pathogens

Abstract

Multidrug-resistant (MDR) pathogens such as Escherichia coli, Pseudomonas aeruginosa, and Enterobacter cloacae have become a global health threat. Drug repositioning or repurposing has become a viable solution to combat the threat posed by MDR pathogens. A strategic approach to identifying potential new candidates as future molecular drug targets is presented in this study. Fifty proteins critical for virulence during systemic infection were selected from the entire genomes of MDR E. coli MB641 and Enterobacter cloacae MB649, which were isolated from infected orthopaedic implants. Interaction networks were built using the STRING database to visualise the positioning of the selected virulence proteins in the network space and support their suitability for therapeutic targeting. The two significant virulence proteins FliG and FlhA, which were discovered by network analysis, were suggested as prospective treatment targets. To test the stability of the protein–drug complexes, the preidentified proteins were docked with 10 marketed antibacterial drugs and six phytochemicals. Amikacin, rifampicin, streptomycin, and tetracycline had the best binding interaction and stability for both strains, according to our findings. Molecular dynamic simulation studies were performed for amikacin and catechin at 100 ns. Both hydrophobic and hydrophilic stable contacts were seen in the active sites of amikacin and catechin with new chemical structures. Structural and conformational analysis of the docked protein-ligand complex was done by RMSD which showed stability of the amikacin and catechin complexes, whereas RMSF showed conformational changes. Based on the results, we propose the phytochemical catechin as the best theoretical lead, which may be further experimentally studied for selective inhibition.