Genomics Guided Drug Discovery in Klebsiella pneumoniae: From Target Identification to in-vitro Testing of Lead Compounds

Abstract

Klebsiella pneumoniae is a multidrug-resistant (MDR) pathogen responsible for a wide range of nosocomial and community-acquired infections. The increasing resistance to conventional antibiotics necessitates alternative therapeutic strategies. This study employs a computational and experimental framework to identify potential drug targets and repurpose FDA-approved drugs against K. pneumoniae. A comprehensive pangenome analysis of 500 K. pneumoniae genomes was conducted to identify core and accessory genes. The core genome was subjected to subtractive proteomics to filter essential, virulent, and non-host homologous proteins, resulting in the identification of seven potential drug targets. These targets were further assessed for druggability through molecular docking and molecular dynamics (MD) simulations, with simvastatin, telmisartan, and adapalene emerging as promising candidates. To validate computational findings, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays were performed. Simvastatin exhibited the strongest antibacterial activity, with the lowest MIC (62.5 μg/mL), while telmisartan and adapalene demonstrated moderate inhibition at 125 μg/mL. However, none of the tested drugs achieved complete bacterial eradication at 250 μg/mL, suggesting the need for further optimization and testing at higher concentrations. The study highlights the potential of drug repurposing as a cost-effective strategy to combat MDR K. pneumoniae infections. Future research should focus on structural modifications, synergistic drug combinations, and clinical evaluations to enhance therapeutic efficacy. This integrated approach provides a valuable roadmap for advancing drug discovery against antibiotic-resistant bacterial pathogens.