Molecular Dynamics Simulation Study On The Interaction Between β-lactamase And β-lactams

Antibiotic resistance has become the one of the major problems worldwide since the first antimicrobial-penicillin was used in clinical. The production of p-lactamase is one of the main reasons for bacterial resistance to P-lactams. Up to now, the species of β-lactamase has reached more than two hundred, and numerous classes of β-lactams are currently available for the treatment of patient with infections. However, the development of β-lactams has been from the penicillin to the cephalosporins, carbapenems and monobactams which are more powerful to the bacterial. Most of these antimicrobials can’t achieve the desired effect especially when facing the novel strains generated by some patients in hospital. So, to get a better understanding about the binding mode between β-lactamase and β-lactams is significant for finding out the reasons for bacterial resistance and the future rational design of novel β-lactams. Here, we studied the interaction mechanism between β-lactamase and P-lactams by using molecular dynamics simulations.1. We chose the monobactams-aztreonam as the ligand and TEM β-lactamase as the drug target. The purpose of this part is to explore the altered binding affinity mechanism of the complex when the TEM β-lactamase bound with G238S/E240K(R) mutation. After the studied mutations, the electrostatic potential of binding pocket changed and hydrogen bonding interactions enhanced. These increased binding affinity of the complexes, so that aztreonam stayed in the cytosolic space and can’t arrive at PBPs.2. We aimed at elucidating different binding mechanisms of CTX-M β-lactamase binding with different β-lactams. Five different β-lactams were chosen inlcuding penicillin, piperacillin, cefotaxime, ceftazidime and aztreonam. The calculated results indicated that binding affinity of β-lactamse-cefotaxime was the strongest in five complexes; hydrogen interactions of β-lactamse bound with piperacilin, cefotaxime and ceftazidime were stronger than the others; residues Ser70, Tyr105, Ser130, Thr216, Thr235, Gly236and Ser237played an important role in binding with ligand.