In-silico Approach Explains Evolution of Beta-lactamases from Penicillin Binding Proteins

Abstract

Penicillin binding proteins (PBPs) possess transpeptidase, transglycosylase as well as carboxypeptidase activities and mediates the crosslinking of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) of peptidoglycan, thereby promoting the cell wall synthesis. The β-lactam antibiotics bind to PBPs and inactivate them, thus killing the bacteria. During the course of evolution, bacteria have also developed differential survival strategies. Emergence of multidrug resistance resulting from β-lactamases constitutes a worldwide threat. This enzyme hydrolyzes β-lactam antibiotics and thus makes them inactive. The purpose of this study was to analyze the binding affinity of β-lactam antibiotics with PBPs and β-lactamases by computational docking studies. For this, different classes of β-lactams known till date were used as ligand for molecular interaction. Computational analysis was performed using GLIDE based on scoring functions. The binding affinity pattern was determined in terms of their binding energies. The results demonstrated that most of the β-lactam antibiotics interact with both β-lactamases and PBPs, which reveals a possible ancestry between β-lactamases and PBPs as both recognize common substrates. Therefore, present work may be helpful in the study of evolutionary relationship between β-lactamases and PBPs at catalytic level.