Structure and molecular recognition mechanism of IMP-13 metallo-β-lactamase

Charlotte A. Softley, Krzysztof M. Zak, Mark J. Bostock, Roberto Fino, Richard Xu Zhou, Marta Kolonko, Ramona Mejdi-Nitiu, Hannelore Meyer, Michael Sattler, Grzegorz M. Popowicz

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Multidrug resistance among Gram-negative bacteria is a major global public health threat. Metallo-β-lactamases (MBLs) target the most widely used antibiotic class, the β-lactams, including the most recent generation of carbapenems. Interspecies spread renders these enzymes a serious clinical threat, and there are no clinically available inhibitors. We present the crystal structures of IMP-13, a structurally uncharacterized MBL from the Gram-negative bacterium Pseudomonas aeruginosa found in clinical outbreaks globally, and characterize the binding using solution nuclear magnetic resonance spectroscopy and molecular dynamics simulations. The crystal structures of apo IMP-13 and IMP-13 bound to four clinically relevant carbapenem antibiotics (doripenem, ertapenem, imipenem, and meropenem) are presented. Active-site plasticity and the active-site loop, where a tryptophan residue stabilizes the antibiotic core scaffold, are essential to the substrate-binding mechanism. The conserved carbapenem scaffold plays the most significant role in IMP-13 binding, explaining the broad substrate specificity. The observed plasticity and substrate-locking mechanism provide opportunities for rational drug design of novel metallo-β-lactamase inhibitors, essential in the fight against antibiotic resistance.

Original languageEnglish
Article numbere00123-20
JournalAntimicrobial Agents and Chemotherapy
Volume64
Issue number6
DOIs
StatePublished - Jun 2020

Keywords

  • Antibiotic resistance
  • IMP-13
  • Imipenemase
  • Metallo-β-lactamase
  • Metalloenzyme
  • Molecular dynamics
  • Nuclear magnetic resonance
  • Protein dynamics
  • Solution NMR
  • X-ray crystallography
  • β-lactam antibiotic

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