In-silico modeling of a novel OXA-51 from β-lactam-resistant Acinetobacter baumannii and its interaction with various antibiotics

J Mol Model. 2012 Jul;18(7):3351-61. doi: 10.1007/s00894-011-1346-3. Epub 2012 Jan 22.

Abstract

Acinetobacter baumannii, one of the major Gram negative bacteria, causes nosocomial infections such as pneumonia, urinary tract infection, meningitis, etc. β-lactam-based antibiotics like penicillin are used conventionally to treat infections of A. baumannii; however, they are becoming progressively less effective as the bacterium produces diverse types of β-lactamases to inactivate the antibiotics. We have recently identified a novel β-lactamase, OXA-51 from clinical strains of A. baumannii from our hospital. In the present study, we generated the structure of OXA-51 using MODELLER9v7 and studied the interaction of OXA-51 with a number of β-lactams (penicillin, oxacillin, ceftazidime, aztreonam and imipenem) using two independent programs: GLIDE and GOLD. Based on the results of different binding parameters and number of hydrogen bonds, interaction of OXA-51 was found to be maximum with ceftazidime and lowest with imipenem. Further, molecular dynamics simulation results also support this fact. The lowest binding affinity of imipenem to OXA-51 indicates clearly that it is not efficiently cleaved by OXA-51, thus explaining its high potency against resistant A. baumannii. This finding is supported by experimental results from minimum inhibitory concentration analysis and transmission electron microscopy. It can be concluded that carbapenems (imipenem) are presently effective β-lactam antibiotics against resistant strains of A. baumannii harbouring OXA-51. The results presented here could be useful in designing more effective derivatives of carbapenem.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinetobacter baumannii / drug effects
  • Acinetobacter baumannii / enzymology*
  • Acinetobacter baumannii / ultrastructure
  • Amino Acid Sequence
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / metabolism
  • Catalytic Domain
  • Drug Resistance, Bacterial
  • Hydrogen Bonding
  • Molecular Dynamics Simulation*
  • Molecular Sequence Data
  • Protein Binding
  • Protein Conformation
  • beta-Lactamases / chemistry*
  • beta-Lactamases / metabolism
  • beta-Lactams / chemistry

Substances

  • Anti-Bacterial Agents
  • beta-Lactams
  • beta-Lactamases