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Antimicrob Agents Chemother. 2020 Mar 23. pii: AAC.00123-20. doi: 10.1128/AAC.00123-20. [Epub ahead of print]

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

Author information

1
Biomolecular NMR and Center for Integrated Protein Science Munich at Department Chemie, Technical University of Munich, Lichtenbergstraße 4, 85747, Garching, Germany.
2
Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
3
Department of Biochemistry, Faculty of Chemistry, Wroclaw University of Science and Technology, Wybrzeze Wyspianskiego 27, 50-370, Wroclaw, Poland.
4
Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Trogerstraße 30, 81675 München, Germany.
5
Biomolecular NMR and Center for Integrated Protein Science Munich at Department Chemie, Technical University of Munich, Lichtenbergstraße 4, 85747, Garching, Germany. grzegorz.popowicz@helmholtz-muenchen.de michael.sattler@helmholtz-muenchen.de.

Abstract

Multi-drug 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 carbapenems. Interspecies spread renders these enzymes a serious clinical threat and there are no clinically-available inhibitors. We present crystal structures of IMP-13, a structurally-uncharacterized MBL from Gram-negative Pseudomonas aerugionasa found in clinical outbreaks globally, and characterize the binding using solution NMR-spectroscopy and molecular-dynamics simulations. Crystal structures of apo IMP-13 and 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.

PMID:
32205343
DOI:
10.1128/AAC.00123-20

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