title: An in silico approach for understanding the molecular evolution of clinically important metallo-beta-lactamases.
abstract: Resistance to carbapenem, considered to be the drug of last resort for treating serious enterobacterial infections, is a growing problem. Metallo-beta-lactamase (MBL) mediated carbapenem resistance is considered to be clinically most important, since no traditional inhibitors work against them. Hence, we have investigated the changes in drug profile, affinity and binding stability of meropenem with clinically important MBLs viz., IMP, VIM and NDM during the course of molecular evolution. Phylogenetic trees were constructed and amino acids positions, presumed to be exposed to positive selection pressure were analyzed. Based on sequence diversity and selection pressure, IMP-1, IMP-8, IMP-9, IMP-21, IMP-27, IMP-20 and IMP-26 among IMP genes; VIM-1, VIM-2, VIM-13, VIM-29, VIM-18 and VIM-7 among VIM genes and NDM-1 had been selected for in silico analysis. Mode of interaction of selected MBL variants with meropenem were analyzed by Autodock4.0 and LIGPLOT analysis. In all the trajectories, we had found an increase in mouth opening/solvent accessible volume/area of the catalytic pocket and decrease in Gibbs' free energy (ΔG°) for binding with meropenem and Michealis-Menten constant (Km) - indicating an increase in choice of drugs, binding stability and meropenem affinity from primitive to advanced MBL variants, with exceptions of IMP-20, IMP-26, VIM-13 and VIM-18 which might be due to sign epistasis. Intergenic comparison revealed NDM-1 might have greater drug profile and catalytic efficiency than IMP-1 and VIM-2 due to largest pocket opening and least distance between the Zn-I ion and β-lactam oxygen of meropenem.
authors: Department of Biochemistry and Medical Biotechnology, Calcutta School of Tropical Medicine, 108, C.R. Avenue, Kolkata 700 073, India. Electronic address: ari.presi.bkp@gmail.com.
authors: Arijit
authors: A
authors: Pal
authors: Anusri
authors: A
authors: Tripathi
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001665:Binding Sites; D015780:Carbapenems / Q000494:pharmacology; D004756:Enterobacteriaceae Infections / Q000188:drug therapy / Q000235:genetics*; D019143:Evolution, Molecular; D006801:Humans; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D010802:Phylogeny; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000648:ultrastructure*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D013845:Thienamycins / Q000494:pharmacology; D018440:beta-Lactam Resistance / Q000235:genetics*; D001618:beta-Lactamases / Q000235:genetics*
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D011956:Receptors, Cell Surface; D013845:Thienamycins; D001618:beta-Lactamases; D000077731:Meropenem
keywords: Binding stability; Evolutionary trajectory; IMP/VIM/NDM; Meropenem affinity; Metallo-beta-lactamase