Molecular Basis of Substrate Recognition and Product Release by the Klebsiella pneumoniae Carbapenemase (KPC-2)

doi:https://doi.org/10.1021/acs.jmedchem.7b00158

Title: Molecular Basis of Substrate Recognition and Product Release by the Klebsiella pneumoniae Carbapenemase (KPC-2)

Abstract

Carbapenem-resistant Enterobacteriaceae are resistant to most β-lactam antibiotics due to the production of the Klebsiella pneumoniae carbapenemase (KPC-2) class A β-lactamase. Here, we present the first product complex crystal structures of KPC-2 with β-lactam antibiotics containing hydrolyzed cefotaxime and faropenem. They provide experimental insights into substrate recognition by KPC-2 and its unique cephalosporinase/carbapenemase activity. These structures also represent the first product complexes for a wild-type serine β-lactamase, elucidating the product release mechanism of these enzymes in general.

Authors:

Pemberton, Orville A. ^[1]; Zhang, Xiujun ^[1];

^[1]

Univ. of South Florida, Tampa, FL (United States)

Publication Date:: 2017-04-17

Research Org.:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Org.:: National Institutes of Health (NIH)

OSTI Identifier:: 1368248

Grant/Contract Number:: AI103158

Resource Type:: Journal Article: Accepted Manuscript

Journal Name:: Journal of Medicinal Chemistry

Additional Journal Information:: Journal Volume: 60; Journal Issue: 8; Journal ID: ISSN 0022-2623

Publisher:: American Chemical Society (ACS)

Country of Publication:: United States

Language:: ENGLISH

Subject:: 59 BASIC BIOLOGICAL SCIENCES; Antimicrobial agents; Peptides and proteins; Monomers; Chemical structure; Conformation

Citation Formats


                    Pemberton, Orville A., Zhang, Xiujun, and Chen, Yu. Molecular Basis of Substrate Recognition and Product Release by the Klebsiella pneumoniae Carbapenemase (KPC-2).  United States: N. p., 2017. 
        Web.  doi:10.1021/acs.jmedchem.7b00158.

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                    Pemberton, Orville A., Zhang, Xiujun, & Chen, Yu. Molecular Basis of Substrate Recognition and Product Release by the Klebsiella pneumoniae Carbapenemase (KPC-2).  United States.  https://doi.org/10.1021/acs.jmedchem.7b00158

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                    Pemberton, Orville A., Zhang, Xiujun, and Chen, Yu. Mon .  
        "Molecular Basis of Substrate Recognition and Product Release by the Klebsiella pneumoniae Carbapenemase (KPC-2)".  United States.  https://doi.org/10.1021/acs.jmedchem.7b00158.  https://www.osti.gov/servlets/purl/1368248.

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@article{osti_1368248,

  title        = {Molecular Basis of Substrate Recognition and Product Release by the Klebsiella pneumoniae Carbapenemase (KPC-2)},

  author       = {Pemberton, Orville A. and Zhang, Xiujun and Chen, Yu},

  abstractNote = {Carbapenem-resistant Enterobacteriaceae are resistant to most β-lactam antibiotics due to the production of the Klebsiella pneumoniae carbapenemase (KPC-2) class A β-lactamase. Here, we present the first product complex crystal structures of KPC-2 with β-lactam antibiotics containing hydrolyzed cefotaxime and faropenem. They provide experimental insights into substrate recognition by KPC-2 and its unique cephalosporinase/carbapenemase activity. These structures also represent the first product complexes for a wild-type serine β-lactamase, elucidating the product release mechanism of these enzymes in general.},

  doi          = {10.1021/acs.jmedchem.7b00158},

  url          = {https://www.osti.gov/biblio/1368248},
  journal      = {Journal of Medicinal Chemistry},

  issn         = {0022-2623},

  number       = 8,

  volume       = 60,

  place        = {United States},

  year         = {2017},

  month        = {4}

}

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Journal Article:

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https://doi.org/10.1021/acs.jmedchem.7b00158

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Cited by: 19 works

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Works referencing / citing this record:

Unravelling ceftazidime/avibactam resistance of KPC-28, a KPC-2 variant lacking carbapenemase activity
journal, May 2019

Oueslati, Saoussen; Iorga, Bogdan I.; Tlili, Linda
Journal of Antimicrobial Chemotherapy, Vol. 74, Issue 8
https://doi.org/10.1093/jac/dkz209

Mechanistic Insights into β-Lactamase-Catalysed Carbapenem Degradation Through Product Characterisation
journal, September 2019

Lohans, Christopher T.; Freeman, Emily I.; Groesen, Emma van
Scientific Reports, Vol. 9, Issue 1
https://doi.org/10.1038/s41598-019-49264-0

Cyclic boronates as versatile scaffolds for KPC-2 β-lactamase inhibition
journal, January 2020

Tooke, Catherine L.; Hinchliffe, Philip; Krajnc, Alen
RSC Medicinal Chemistry, Vol. 11, Issue 4
https://doi.org/10.1039/c9md00557a

Molecular Basis of Class A β-Lactamase Inhibition by Relebactam
journal, August 2019

Tooke, Catherine L.; Hinchliffe, Philip; Lang, Pauline A.
Antimicrobial Agents and Chemotherapy, Vol. 63, Issue 10
https://doi.org/10.1128/aac.00564-19

Antibacterial Spectrum of a Tetrazole-Based Reversible Inhibitor of Serine β-Lactamases
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Pemberton, Orville A.; Zhang, Xiujun; Nichols, Derek A.
Antimicrobial Agents and Chemotherapy, Vol. 62, Issue 8
https://doi.org/10.1128/aac.02563-17

Influence of substrates and inhibitors on the structure of Klebsiella pneumoniae carbapenemase-2
journal, June 2019

Shurina, Ben A.; Page, Richard C.
Experimental Biology and Medicine, Vol. 244, Issue 17
https://doi.org/10.1177/1535370219854322

In silico identification and experimental validation of hits active against KPC-2 β-lactamase
journal, November 2018

Klein, Raphael; Linciano, Pasquale; Celenza, Giuseppe
PLOS ONE, Vol. 13, Issue 11
https://doi.org/10.1371/journal.pone.0203241

Phenylboronic Acids Probing Molecular Recognition against Class A and Class C β-lactamases
journal, September 2019

Linciano, Pasquale; Vicario, Mattia; Kekez, Ivana
Antibiotics, Vol. 8, Issue 4
https://doi.org/10.3390/antibiotics8040171

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Similar Records

Title: Molecular Basis of Substrate Recognition and Product Release by the Klebsiella pneumoniae Carbapenemase (KPC-2)

Abstract

Citation Formats

Unravelling ceftazidime/avibactam resistance of KPC-28, a KPC-2 variant lacking carbapenemase activity journal, May 2019

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Antibacterial Spectrum of a Tetrazole-Based Reversible Inhibitor of Serine β-Lactamases journal, May 2018

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Phenylboronic Acids Probing Molecular Recognition against Class A and Class C β-lactamases journal, September 2019

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journal, May 2019

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