A Computational Approach for The Use of Phytocompounds as a Drug Candidate Against Carbapenemase Producing Klebsiella pneumoniae

Abstract

There is a rapid evolution and spread of carbapenem resistant bacteria through horizontal gene transfer of the genes encoding production of carbapenemases leading to the colonization of resistant Klebsiella pneumoniae (K. pneumoniae) in human. This is one of the major causes of hospital-acquired infections that are difficult to treat due to the production of carbapenamases that destroys the carbapenem antibiotics. Therefore, there is an urgent need to accelerate the discovery of antimicrobials for the effective treatment of these diseases.  In silico studies are proffered as novel approaches in drug discovery to curb and alleviate diseases by identifying and characterizing potential lead compounds. This study utilized this approach to characterize carbapenemase inhibitors from natural compounds. Molecular docking (MD) and molecular dynamics and simulations (MDS) were used to profile 105 natural compounds against the K. pneumoniae carbapenemase (KPC-2). The compounds (ligands), were docked to KPC-2 (PDB ID: 2OV5) as the receptor. After the virtual screening, 24 of these phytocompounds had better inhibitory activity against KPC-2 than the co-crystallized ligand (Bicine) while 18 had higher binding affinity than the Imipenem that was used as the reference antibiotic. Hypericin, WithaferinA, Eriodictyol-7-O-glucoside and Glabidrin had the best docking scores of -10.6, -9.5, -8.8 and -8.5 Kcal/Mol respectively.  Only WithaferinA, Eriodictyol-7-O-glucoside and Glabidrin bound to the active amino acid residues of the KPC-2 while ADMET studies favoured Glabridin with good profiles. MDS of the Glabridin also proved good inhibition of KPC-2 at the active site. Glabridin would be a useful drug candidate in the design of novel KPC inhibitors. Withaferin A and Eriodictyol-7-O-glucoside could also be optimized for better ADMET properties. Naturally occurring phytocompound could serve as solution to the effective treatment of resistance caused by carbapenem resistant Klebsiella pneumoniae. Further in-vitro studies are required to evaluate and confirm the potential of phytocompounds as anti-KPC-2 inhibitors.