Biplab Bhattacharjee1, Priya Prakash1, Rukmini Jonnalagadda1, BM Arpitha1, Jhinuk Chatterjee1, V Krishna Murthy1, Jayadev Joshi2
1Department of Biotechnology, PES Institute of Technology, Bangalore, India.
2Radiation Biosciences Group, Institute of Nuclear Medicine & Allied Sciences (INMAS) – DRDO, New Delhi, India.


New Delhi metallo beta lactamase-1 – Klebsiella pneumonia or superbug has become a global menace because of its high resistivity to all generation of antibiotics, including carbapenams – one of the antibiotics of last resort for many bacterial infections. There have been recent cases of horizontal gene transfer of NDM-1 gene from Klebsiella pneumonia to other microbes giving rise to new generation of antibiotic resistant microbes. NDM-1 also has a potent ability to “eat out” carbapenemase as its active site is much larger than those of the normal strains. In this review, we have used Insilico approaches in finding structural analogs to block the active site of NDM-1 enzyme allowing normal antibiotics to act on other drug targets in these bacteria. In this study, we have come across a rare case of a bacterial enzyme which has a large active site in comparison to normal strains. Phytochemicals having a larger structure to ensure a good fit in the active site were chosen for screening. About 1200 plus natural and synthetic ligands from PubChem & ZINC database were screened against the beta lactamase-1 enzyme. Beta lactamase-1 enzyme structure was retrieved from RCSB-PDB (PDB ID – 3RKK). Autodock Vina was used to conduct the Ligand-Protein interaction studies. We needed a competitive ligand with a higher binding affinity than carbapenams for the active site. Molecular Dynamics studies were done using GROMACS to see the simulated state of binding pose. IC50 predictions were done using Quantum 3.30 to rank the ligands based on their inhibition capabilities. The Linear Regression Coefficient (r) between the GBind Score and the IC50 datasets of the first 10 ranked ligands was also calculated. We identified some phytochemicals which had a high binding affinity towards the active site of beta lactamase 1 enzyme. The H-bond interaction between the ligand and the amino acids contributing to the active site was observed. The H-Bond distance was found to be less than 4 Angstrom depicting it as closely knit interactions. Molecular dynamics simulations also revealed the stability of the binding pose. The Regression coefficient value between GBind Score and IC50 was close to 1 revealing a linear relationship between binding affinity and inhibition potential. We are conducting further studies on isolation and purification of these phytochemicals in experimental laboratory and testing its inhibition ability real time.

Further studies need to be carried out to confirm whether the combinational therapy of phytochemicals & antibiotics eliminates the antibiotic resistance of these strains.Read more…

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