Molecular evolution of carbapenemases KPC-12 and molecular docking analysis of β-lactams / 中华临床感染病杂志

ABSTRACT

Objective To analyze molecular evolution of carbapenemase KPC-12 and its binding free energies with β-lactams.Methods Class A beta-lactamases were divided into 2 clustersthose with carbapenemase activities and those without.Minimum Evolution method in MEGA4.1 software was used to analyze molecular evolution of class A beta-lactamases with carbapenemase activity,including KPC-2 to KPC-13,SFC-1,SME-1,IMI-1,NMC-A,and class A beta-lactamases without carbapenemase activity,including TEM-1,SHV-1.Then,tertiary structure of KPC-12 was predicted by homology modeling as reported in SWISS-MODEL database depending on tertiary structure of KPC-2.Moreover,DOCK module in ArgusLab 4.1 software was used to perform molecular docking of KPC-12 to 10 kinds of beta-lactams substrates,and the binding free energies (△ G) were calculated.Results Molecular evolution between KPC-12 and KPC-2 was the closest.The top three decline in binding free energies of β-lactams were penicillin G sodium salt (△G =-8.45149 kcal/mol),ertapenem (△G =-8.36383 kcal/mol) and ampicillin (△G =-8.19326 kcal/mol),while the last two decline in binding free energies of β-lactams were aztreonam (△G =-6.50614 kca]/mol) and clavulanic acid (△G =-6.88533 kcal/mol).Conclusion Carbapenemase KPC-12 has high catalytic activities to penicillin G sodium salt,ertapenem and ampicillin,while has low catalytic activities to aztreonam and clavulanic acid.