Pangenome Analysis of Klebsiella pneumoniae isolates Reveals Core-Drug Targets and Screening of Promising Lead Compounds for Drug Discovery

Abstract

A Gram-negative, non-motile bacterium called Klebsiella pneumoniae poses a severe threat to the public's health and frequently causes opportunistic infections in hospital patients that are resistant to antibiotics. It is a widespread bacterium that is a major cause of multidrug-resistant health-related infections. K. pneumoniae is usually found in the gastrointestinal system in humans, with a few unusual cases in the nasophryrnx where it can infect other tissues and enter into bloodstream leading illness. In the pre antibiotic period, Klebsiella pneumoniae was a significant pathogen of community acquired pneumonia (CAP), particularly in diabetics and those who consume alcohol. Major community-acquired hypervirulent Kp disorder, commonly characterized as a pyogenic liver abscess with associated bacteremia, but also meningitis, brain abscess, or opthalmitis1, has emerged in the past three decades. Since then, Carbapenem resistant K. pneumoniae (CRKP) has been regularly detected in various nosocomial settings around the world. A wide range of antibiotics, such as β-lactams and aminoglycosides, are involved in controlling and treating K. pneumoniae-related infections. The presence of a substantial number of fully sequenced genomes of Klebsiella pneumoniae has created a chance to investigate the specie’s pan genomes as well as phylogenetic history and to establish fresh innovative drug targets contributing to drug discovery efforts. In order to identify primary drug targets that are susceptible to antibiotics, this study uses a bioinformatics framework that includes pan-genomics, subtractive proteomics, and reverse vaccination strategies. In this study, pangenome analysis and subtractive proteomics were performed on the 560 complete genomes that make up the pangenome of this concerning pathogen. Additionally, subtractive proteomics apply with subsequent filters such as (non human homology, essentiality assessment, virulence evaluation, physiochemical checks, and pathways analysis).Furthermore, the conserved core genome will undergo several different filters, such as essentiality, non-homology, virulence, physiochemical analysis, localization, and pathway analysis are applied to the core proteome (617 proteins), resulting in the identification of five potential core drug targets with a wide therapeutic window. Additionally, the FDA's molecular docking analysis of these drugs targets five promising ligands that were found using both approved and unapproved ligands from the Drug Bank database namely Phosphoaminophosphonic Acid-Adenylate Ester, formic acid, Vitamin E, Thymidine cyclophosphate, and Doxorubicin. Future research could experimentally validate the potential drug targets, helping with the development of new medications.