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Softley, C. ; Zak, K.M.* ; Bostock, M.J. ; Fino, R. ; Zhou, R.X. ; Kolonko, M. ; Mejdi-Nitiu, R.* ; Meyer, H.* ; Sattler, M. ; Popowicz, G.M.

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

Antimicrob. Agents Chemother. 64:e00123-20 (2020)
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Multidrug resistance among Gram-negative bacteria is a major global public health threat. Metallo-beta-lactamases (MBLs) target the most widely used antibiotic class, the beta-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-beta-lactamase inhibitors, essential in the fight against antibiotic resistance.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Imp-13 ; Metallo-beta-lactamase ; Imipenemase ; Antibiotic Resistance ; Solution Nmr ; X-ray Crystallography ; Molecular Dynamics ; Metalloenzyme ; Protein Dynamics ; Beta-lactam Antibiotic ; Nuclear Magnetic Resonance; Active-site Loop; Pseudomonas-aeruginosa; Bacteroides-fragilis; Crystal-structure; Gene Bla(imp); Binding; Protein; Resistant; Inhibitor; Dynamics
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 0066-4804
e-ISSN 1098-6596
Journal Antimicrobial Agents and Chemotherapy
Quellenangaben Volume: 64, Issue: 6, Pages: , Article Number: e00123-20 Supplement: ,
Publisher American Society for Microbiology (ASM)
Publishing Place 1752 N St Nw, Washington, Dc 20036-2904 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-503000-001
DOI 10.1128/AAC.00123-20
WOS ID WOS:000535946300006
Scopus ID 85085265617
PubMed ID 32205343
Erfassungsdatum 2020-04-02
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