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Testing the Role of Multicopy Plasmids in the Evolution of Antibiotic Resistance
09:00

Testing the Role of Multicopy Plasmids in the Evolution of Antibiotic Resistance

Published on: May 2, 2018

The sequence-activity relationship between metallo-β-lactamases IMP-1, IMP-6, and IMP-25 suggests an evolutionary

Eleanor M Liu1, Kevin M Pegg, Peter Oelschlaeger

  • 1Department of Pharmaceutical Sciences, Western University of Health Sciences, Pomona, CA, USA.

Antimicrobial Agents and Chemotherapy
|September 26, 2012
PubMed

Insights

Metallo-β-lactamases (MBLs) confer antibacterial resistance. IMP-1 is broadly active, while IMP-6 and IMP-25 specifically target meropenem, potentially due to a G235S mutation influencing enzyme activity.

Area of Science:

  • Microbiology
  • Biochemistry
  • Structural Biology

Background:

  • Metallo-β-lactamases (MBLs) are critical enzymes mediating bacterial resistance to β-lactam antibiotics.
  • Understanding the structure-activity relationships of MBLs is crucial for developing novel therapeutic strategies.

Purpose of the Study:

  • To investigate the sequence-activity relationship among closely related MBLs: IMP-1, IMP-6, and IMP-25.
  • To elucidate the molecular basis for differential substrate specificities, particularly concerning carbapenem inactivation.

Main Methods:

  • Enzyme activity assays across a spectrum of β-lactam antibiotics.
  • Molecular modeling to analyze structural differences and their potential impact on enzyme function.

Main Results:

  • IMP-1 exhibits broader activity against various β-lactam agents.
  • IMP-6 and IMP-25 demonstrate enhanced specificity for inactivating the carbapenem meropenem.
  • Molecular modeling suggests the G235S mutation in IMP-25 influences activity, potentially through interactions with Asn233.

Conclusions:

  • IMP-1, IMP-6, and IMP-25 display distinct substrate profiles, highlighting evolutionary divergence in MBLs.
  • The G235S mutation is a key factor in the carbapenem-specific activity of IMP-25.
  • These findings provide insights into MBL resistance mechanisms and potential targets for antimicrobial drug development.

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