Related Experiment Video

Updated: Dec 25, 2025

The Use of a β-lactamase-based Conductimetric Biosensor Assay to Detect Biomolecular Interactions
08:06

The Use of a β-lactamase-based Conductimetric Biosensor Assay to Detect Biomolecular Interactions

Published on: February 1, 2018

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Structure and Molecular Recognition Mechanism of IMP-13 Metallo-β-Lactamase

Charlotte A Softley1,2, Krzysztof M Zak2, Mark J Bostock1,2

  • 1Biomolecular NMR and Center for Integrated Protein Science Munich at Department Chemie, Technical University of Munich, Garching, Germany.

Antimicrobial Agents and Chemotherapy
|March 25, 2020
PubMed

Insights

Metallo-β-lactamases (MBLs) like IMP-13 are a major threat, resisting carbapenem antibiotics. Understanding IMP-13

Area of Science:

  • Structural Biology
  • Microbiology
  • Drug Discovery

Background:

  • Multidrug resistance in Gram-negative bacteria, particularly due to metallo-β-lactamases (MBLs), poses a significant global health challenge.
  • MBLs inactivate β-lactam antibiotics, including carbapenems, with limited therapeutic options and no available inhibitors.
  • The MBL IMP-13, identified in *Pseudomonas aeruginosa* clinical outbreaks, requires structural and functional characterization.

Purpose of the Study:

  • To elucidate the crystal structures of the metallo-β-lactamase IMP-13.
  • To characterize the binding mechanism of IMP-13 with clinically relevant carbapenem antibiotics.
  • To identify potential targets for novel inhibitor design against MBL-mediated antibiotic resistance.

Main Methods:

  • X-ray crystallography was employed to determine the structures of apo IMP-13 and IMP-13 bound to doripenem, ertapenem, imipenem, and meropenem.
  • Solution nuclear magnetic resonance (NMR) spectroscopy was used to characterize substrate binding.
  • Molecular dynamics simulations were performed to analyze the binding interactions and active-site dynamics.

Main Results:

  • Crystal structures revealed IMP-13's active-site plasticity and the crucial role of a tryptophan residue in stabilizing the carbapenem core.
  • The conserved carbapenem scaffold is the primary determinant of IMP-13 binding, explaining its broad substrate specificity.
  • Analysis highlighted a substrate-locking mechanism essential for enzyme-antibiotic interaction.

Conclusions:

  • The structural and mechanistic insights into IMP-13 binding provide a foundation for rational drug design.
  • Targeting the observed plasticity and substrate-locking mechanism could lead to novel inhibitors against MBLs.
  • Developing new inhibitors is critical to combat the growing threat of carbapenem resistance in Gram-negative bacteria.
Keywords:
IMP-13X-ray crystallographyantibiotic resistanceimipenemasemetallo-β-lactamasemetalloenzymemolecular dynamicsnuclear magnetic resonanceprotein dynamicssolution NMRβ-lactam antibiotic

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