In silico structural analysis of carbapenemase variants in Klebsiella pneumoniae: insights for precision drug discovery against multidrug-resistant strains.

BACKGROUND

Carbapenemase-producing Klebsiella pneumoniae severely limits treatment options by inactivating carbapenem and other β-lactam antibiotics. To support precision drug discovery, this study investigates how structural and dynamic differences among major carbapenemase families shape their interaction with carbapenem drugs.

RESEARCH DESIGN AND

METHODS

The authors performed an in-silico analysis of five key Klebsiella pneumoniae carbapenemases (KPC, NDM, VIM, IMP, OXA-48) using multiple sequence alignment, homology modeling, molecular docking, and 50-ns molecular dynamics simulations.

RESULTS

Sequence identity between variants was low (33.8-48.5%), indicating deep evolutionary divergence. SWISS-MODEL homology models showed high stereochemical quality, supporting reliable active-site interpretation. Docking suggested stronger binding of meropenem and imipenem to KPC and NDM, mediated by conserved catalytic residues in class A (Ser70, Lys73, Glu166) and class B (His120, His122, Asp124). MD simulations indicated more rigid, compact complexes for KPC and NDM, contrasted with higher flexibility in OXA-48.

CONCLUSIONS

These results reinforce that Klebsiella pneumoniae carbapenemases are not interchangeable targets and that inhibitor design must account for family-specific active-site geometries and dynamics. Integrating such structural insight with future virtual screening and experimental validation could enable variant-tailored inhibitors rather than relying on a single broad-spectrum carbapenemase blocker.