title: Structure-based screening of inhibitors against KPC-2: designing potential drug candidates against multidrug-resistant bacteria.
abstract: KPC-2 β-lactamase demonstrates a wide substrate spectrum that includes carbapenamases, oxyimino-cephalosporins, and cephamycins. In addition, strains harboring KPC-type β-lactamases are often identified as resistant to standard β-lactamase inhibitors. Thus, KPC-2 carbapenems present a significant clinical challenge, as the mechanistic bases for KPC-2-associated phenotypes remain mysterious. Inhibiting the function of these resistance enzymes could control the hydrolysis of antibiotics. In the present study, we have reported two novel (non-β-lactatam) compounds that inhibit the activity of the KPC-2 enzyme. These compounds were identified by structure-based virtual screening using computational docking programs and molecular dynamics simulations with the solved crystal structure. Two compounds (ZINC01807204 and ZINC02318494) were selected on the basis of fitness scores from docking program and 5 ns molecular dynamics simulations. These commercially available compounds have been procured and their biological activity was experimentally evaluated on the E. coli strain carrying recombinant KPC-2. These new compounds in combination with ceftazidime and cefoxitin exhibited the Minimum Inhibitory Concentration (MIC) values of 2 and 8 μg/ml respectively, which were found to be lower as compared to known β-lactamase inhibitors. Moreover, these compounds were also found to have comparable MICs values being 64 μg/ml in combination with ceftriaxone. This study explored novel inhibitors against KPC-2, a class A β-lactamase, which may be putative drug candidates against KPC-2 producing bacterial infection.
authors.affiliation: a Interdisciplinary Biotechnology Unit, AMU , Aligarh , 202002 , India .
authors.forename: Mohd
authors.initials: M
authors.lastname: Danishuddin
authors.forename: Arbab
authors.initials: A
authors.lastname: Khan
authors.forename: Mohammad
authors.initials: M
authors.lastname: Faheem
authors.forename: Ponnusamy
authors.initials: P
authors.lastname: Kalaiarasan
authors.forename: Mohd
authors.initials: M
authors.lastname: Hassan Baig
authors.forename: Naidu
authors.initials: N
authors.lastname: Subbarao
authors.forename: Asad U
authors.initials: AU
authors.lastname: Khan
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D015195:Drug Design; D024901:Drug Resistance, Multiple, Bacterial; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D013329:Structure-Activity Relationship; D001618:beta-Lactamases / Q000737:chemistry / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; C491478:beta-lactamase KPC-2; D001618:beta-Lactamases