Dataset Information

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.

SUBMITTER: Softley CA

PROVIDER: S-EPMC7269475 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Publications

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

Softley Charlotte A CA Zak Krzysztof M KM Bostock Mark J MJ Fino Roberto R Zhou Richard Xu RX Kolonko Marta M Mejdi-Nitiu Ramona R Meyer Hannelore H Sattler Michael M Popowicz Grzegorz M GM

Antimicrobial agents and chemotherapy 20200521 6

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 <i>Pseudomonas aeruginosa</i> found ...[more]

PMID: 32205343

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Project description:We recently detected a novel variant of an IMP-type metallo-β-lactamase gene (blaIMP-68) from meropenem-resistant but imipenem-susceptible Klebsiella pneumoniae TA6363 isolated in Tokyo, Japan. blaIMP-68 encodes a Ser262Gly point mutant of IMP-11, and transformation experiments showed that blaIMP-68 increased the MIC of carbapenems in recipient strains, whereas the MIC of imipenem was not greatly increased relative to that of other carbapenems, including meropenem. Kinetics experiments showed that IMP-68 imipenem-hydrolyzing activity was lower than that for other carbapenems, suggesting that the antimicrobial susceptibility profile of TA6363 originated from IMP-68 substrate specificity. Whole-genome sequencing showed that blaIMP-68 is harbored by the class 1 integron located on the IncL/M plasmid pTMTA63632 (88,953 bp), which was transferable via conjugation. The presence of plasmid-borne blaIMP-68 is notable, because it conferred antimicrobial resistance to carbapenems, except for imipenem, on Enterobacteriaceae and will likely affect treatment plans using antibacterial agents in clinical settings.IMPORTANCE IMP-type metallo-β-lactamases comprise one group of the "Big 5" carbapenemases. Here, a novel blaIMP-68 gene encoding IMP-68 (harboring a Ser262Gly point mutant of IMP-11) was discovered from meropenem-resistant but imipenem-susceptible Klebsiella pneumoniae TA6363. The Ser262Gly substitution was previously identified as important for substrate specificity according to a study of other IMP variants, including IMP-6. We confirmed that IMP-68 exhibited weaker imipenem-hydrolyzing activity than that for other carbapenems, demonstrating that the antimicrobial susceptibility profile of TA6363 originated from IMP-68 substrate specificity, with this likely to affect treatment strategies using antibacterial agents in clinical settings. Notably, the carbapenem resistance conferred by IMP-68 was undetectable based on the MIC of imipenem as a carbapenem representative, which demonstrates a comparable antimicrobial susceptibility profile to IMP-6-producing Enterobacteriaceae that previously spread in Japan due to lack of awareness of its existence.

Dataset Information

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

Publications

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

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