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Structure and Molecular Recognition Mechanism of IMP-13 Metallo-?-Lactamase.

ABSTRACT: Multidrug resistance among Gram-negative bacteria is a major global public health threat. Metallo-?-lactamases (MBLs) target the most widely used antibiotic class, the ?-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-?-lactamase inhibitors, essential in the fight against antibiotic resistance.


PROVIDER: S-EPMC7269475 | BioStudies | 2020-01-01

REPOSITORIES: biostudies

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