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.
