Open AccessStructure and Molecular Recognition Mechanism of IMP-13 Metallo-β-Lactamase
Author(s) -
Charlotte Softley,
Krzysztof Żak,
Mark Bostock,
Roberto Fino,
Richard Xu Zhou,
Marta Kolonko,
Ramona Mejdi-Nitiu,
Hannelore Meyer,
Michael Sattler,
Grzegorz M. Popowicz
Publication year - 2020
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.00123-20
Subject(s) - doripenem , ertapenem , pseudomonas aeruginosa , active site , biology , imipenem , meropenem , microbiology and biotechnology , antibiotics , carbapenem , antibiotic resistance , binding site , bacteria , chemistry , biochemistry , enzyme , genetics
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.