Author ORCID Identifier

0000-0002-0811-4673

Date of Award

17-8-2025

Document Type

Thesis

School

School of Chemical & Biotechnology

Programme

Ph.D.-Doctoral of Philosophy

First Advisor

R. Jayapradha

Keywords

Klebsiella pneumonia, Genomes, Antimicrobial Resistance, β-lactamases, Inhibitors

Abstract

Klebsiella pneumoniae is an important ESKAPE pathogen that causes life threatening infections. The strains exhibiting multidrug-resistance (MDR) and hypervirulence are the priority pathogens for which immediate treatment and dissemination prevention strategies are required. To address this, genome profiling was performed to understand the AMR patterns, role of episomes, phages, virulence determinants and its association with sequence types.

The study includes 267 publicly available Indian K. pneumoniae genomes over a period of ten years and four sequenced isolates. Whole genome analysis revealed the widespread presence of diverse β-lactamase genes, with β-lactam resistance being predominant. Genes such as blaCTX-M-15, blaTEM-1B and blaOXA-232 were frequently detected among the study genomes. IncF conjugative plasmids, which play a crucial role in the horizontal transfer of antimicrobial resistance (AMR) genes is abundant in clinical isolates.

Furthermore, the virulence characterization highlighted the frequency of strains with genotype ST231-KL51 and ST23-KL1 associated with hypervirulence. The pangenome of K. pneumoniae was open suggesting high genetic diversity. More than 90% of the resistome and virulome were found in the accessory genome, demonstrating the high transmission rates of genes across the pathogen.

Additionally, fragment-based drug discovery identified four lead compounds (GTMK30, ETXLN28, GTMK4, ETXLN1) with strong interactions against ESBLs and carbapenemases. Alternatively, extracts from actinomycetes species were used to screen for the β-lactamase inhibiting activity. The comparative metabolomics analysis revealed shared metabolites among the extracts having β-lactamase inhibiting activity. xxi This study integrates genomic surveillance with resistance modulator screening, providing a comprehensive understanding of K. pneumoniae’s genomic features and potential therapeutic leads.

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