Therapeutic target identification via differential genome analysis of antibiotic resistant Shigella sonnei and inhibitor evaluation against a selected drug target.

Shigella sonnei has been implicated in bloody diarrhea (accompanied by abdominal pain and fever) and is an emerging pathogen of concern, especially in developing countries. The major means of transmission is the fecal-oral route while sexual transmission has also been reported. In children, the impact might be stunted growth due to life-threatening illness. Resistance has been reported in this species for several types of antibiotics. In this study, we retrieved the antibiotic-resistant labeled whole genome sequences of the species from the PATRIC database and performed a pan-genome analysis to filter out core genes. Antibiotic resistance was studied in the core, accessory and unique genome. Core genes were utilized as seed substance for essentiality analysis and drug candidate assignment. Product of the gene aroG, i.e. chorismate biosynthetic process 3-deoxy-7-phosphoheptulonate synthase enzyme, responsible for aromatic amino acid family biosynthetic process, was taken for further downstream processing. Natural product libraries of flavonoids (n = 178), ZINC database derived inhibitor compounds of the 3-deoxy-7-phosphoheptulonate synthase enzyme (n = 112), and streptomycin compounds (n = 737) were docked to find out potent inhibitors, followed by dynamics simulation of 50 ns each for top compounds.. Physicochemical and ADMET profiling of the top compounds was done to analyze their safety for consumption. We propose that the top compounds: Phytoene from Streptomycin library and ZINC000036444158 (synonym:1,16-bis[(dihydroxyphosphinyl)oxy]hexadecane) from 3-deoxy-7-phosphoheptulonate synthase inhibitor library of ZINC database (and used as a control in this study) should be tested in vitro against Shigella sonnei, to fully determine their efficacy. This could add to the drying pipeline of potent drug molecules against emerging pathogens.

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