Potential Drug Targets Identification Against Clostridioides Difficile (CD) and Characterization of Indispensable Proteins by a Subtractive Genomics Approach Followed by Virtual Screening

Abstract

Background:Clostridioides difficile (CD) is an enteric multi-drug resistant pathogenic bacterium. CD-associated infections are the leading cause of nosocomial diarrhea that can further lead to pseudomembranous colitis, toxic mega-colon or sepsis with greater mortality and morbidity risks. CD infection possesses higher rates of recurrence due to its greater resistance to antibiotics. Considering its higher rates of recurrence, it has become a major burden on healthcare facilities. Therefore, there is a dire need to identify novel drug targets to combat antibiotic resistance of Clostridioides difficile.Objective:To identify and propose new and novel drug targets against the Clostridioides difficile.Methods:In the current study, a computational subtractive genomics approach was applied to obtain a set of potential drug targets that exist in the multi-drug resistant strain of Clostridioides difficile. Here, the uncharacterized proteins were studied as potential drug targets. The methodology involved several bioinformatics databases and tools. The druggable proteins sequences were retrieved based on non-homology with host proteome and essentiality for the survival of the pathogen. The uncharacterized proteins were functionally characterized using different computational tools, and sub-cellular localization was also predicted. The metabolic pathways were analyzed using the KEGG database. Eventually, the druggable proteome has been fetched using sequence similarity with the already available drug targets present in the DrugBank database. These druggable proteins were further explored for the structural details to identify drug candidates.Results :A priority list of potential drug targets was provided with the help of the applied method on the complete proteome set of the C. difficile. Moreover, the drug-like compounds have been screened against the potential drug targets to prioritize potential drug candidates. To facilitate the need for drug targets and therapies, the study proposed five potential protein drug targets, out of which three proposed drug targets were subjected to homology modeling to explore their structural and functional activitiesConclusion:In conclusion, we proposed three unique, unexplored drug targets against C. difficile. The structure-based methods were applied and resulted in a list of top-scoring compounds as potential inhibitors to proposed drug targets.