Mechanistic insights into Rottlerin's inhibition of MrkH-mediated biofilm and capsule formation in Klebsiella pneumoniae
Abstract
Background: Klebsiella pneumoniae is a notoriously aggressive opportunistic pathogen within the Enterobacteriaceae family, with virulence factors, including polysaccharide capsules, lipopolysaccharide (LP>S), siderophores, and biofilm formation, serving as essential determinants of the pathogenicity. Biofilms in particular are associated with substantial nosocomial and community-acquired illnesses; moreover, the capsule enveloping K. pneumoniae's surface further contributes to its viscous phenotype and virulence. This study explores the possible anti-virulence properties of the plant-derived compound Rottlerin using molecular docking aimed at a crucial protein implicated in biofilm formation in Klebsiella pneumoniae. Here, we investigate the molecular foundation of ligand-specific modulation of MrkH, a c-di-GMP-responsive transcriptional activator essential for biofilm development in Klebsiella pneumoniae. Utilizing a comprehensive methodology that encompasses molecular docking, dynamic modeling, and structural analysis, we evaluated the native c-di-GMP dimer-MrkH complex against the binding orientation and conformational impacts of the plant-derived chemical Rottlerin.
Results: The sub-MIC of Rottlerin shows an inhibitory effect against some virulence factors, leading to a 57.6% decrease in biofilm formation, and a reduction in capsule size by 85.6% was observed; moreover, Rottlerin also significantly downregulated genes associated with these virulence factors. Through…
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