Inhibition of a cold-active alkaline phosphatase by imipenem revealed by in silico modeling of metallo-beta-lactamase active sites

Sandeep Chakraborty; Bjarni Asgeirsson; Renu Minda; Lipika Salaye; Jean-Marie Frere; Basuthkar J. Rao

doi:10.1016/j.febslet.2012.08.030

Inhibition of a cold-active alkaline phosphatase by imipenem revealed by in silico modeling of metallo-beta-lactamase active sites

Sandeep Chakraborty, Bjarni Asgeirsson, Renu Minda, Lipika Salaye, Jean-Marie Frere, Basuthkar J. Rao

Faculty of Physical Sciences

University of Iceland

Research output: Contribution to journal › Article › peer-review

Abstract

We demonstrate the inhibition of the native phosphatase activity of a cold active alkaline phosphatase from Vibrio (VAP) (IC₅₀ of 44 ± 4 (n = 4) μM at pH 7.0 after a 30 min preincubation) by a specific β-lactam compound (only by imipenem, and not by ertapenem, meropenem, ampicillin or penicillin G). The homologous scaffold was detected by an in silico analysis that established the spatial and electrostatic congruence of the active site of a Class B2 CphA metallo-β-lactamase from Aeromonas hydrophila to the active site of VAP. The tested β-lactam compounds did not inhibit Escherichia coli or shrimp alkaline phosphatase, which could be ascribed to the lower congruence indicated by CLASP. There was no discernible β-lactamase activity in the tested alkaline phosphatases. This is the first time a scaffold recognizing imipenem in an alkaline phosphatase (VAP) has been demonstrated.

Original language	English
Pages (from-to)	3710-3715
Number of pages	6
Journal	FEBS Letters
Volume	586
Issue number	20
DOIs	https://doi.org/10.1016/j.febslet.2012.08.030
Publication status	Published - 19 Oct 2012

Bibliographical note

Funding Information: B.J.R. would like to thank the Tata Institute of Fundamental Research (Department of Atomic Energy) and Department of Science and Technology (JC Bose Award Grant) for financial support. B.A. extends gratitude to the Icelandic National Research Council (RANNIS) and the University of Iceland Research Fund for supporting the project financially. The work in Liege was supported by an IUAP program funded by the Belgian federal government. The funders had no role in study design, collection, and interpretation of data, writing of the report and in the decision to submit the article for publication.

Other keywords

Active site prediction
Alkaline phosphatase
Antibiotic resistance
Carbapenemases
Cold-active Vibrio
Computational biology
Finite difference Poisson-Boltzmann (FDPB)
Imipenem
Inhibition
Metallo-betalactamase
Promiscuous active site

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10.1016/j.febslet.2012.08.030

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@article{f3e13fb5a90a4cb6a3a80a0ed80ce316,

title = "Inhibition of a cold-active alkaline phosphatase by imipenem revealed by in silico modeling of metallo-beta-lactamase active sites",

abstract = "We demonstrate the inhibition of the native phosphatase activity of a cold active alkaline phosphatase from Vibrio (VAP) (IC50 of 44 ± 4 (n = 4) μM at pH 7.0 after a 30 min preincubation) by a specific β-lactam compound (only by imipenem, and not by ertapenem, meropenem, ampicillin or penicillin G). The homologous scaffold was detected by an in silico analysis that established the spatial and electrostatic congruence of the active site of a Class B2 CphA metallo-β-lactamase from Aeromonas hydrophila to the active site of VAP. The tested β-lactam compounds did not inhibit Escherichia coli or shrimp alkaline phosphatase, which could be ascribed to the lower congruence indicated by CLASP. There was no discernible β-lactamase activity in the tested alkaline phosphatases. This is the first time a scaffold recognizing imipenem in an alkaline phosphatase (VAP) has been demonstrated.",

keywords = "Active site prediction, Alkaline phosphatase, Antibiotic resistance, Carbapenemases, Cold-active Vibrio, Computational biology, Finite difference Poisson-Boltzmann (FDPB), Imipenem, Inhibition, Metallo-betalactamase, Promiscuous active site",

author = "Sandeep Chakraborty and Bjarni Asgeirsson and Renu Minda and Lipika Salaye and Jean-Marie Frere and Rao, \{Basuthkar J.\}",

note = "Funding Information: B.J.R. would like to thank the Tata Institute of Fundamental Research (Department of Atomic Energy) and Department of Science and Technology (JC Bose Award Grant) for financial support. B.A. extends gratitude to the Icelandic National Research Council (RANNIS) and the University of Iceland Research Fund for supporting the project financially. The work in Liege was supported by an IUAP program funded by the Belgian federal government. The funders had no role in study design, collection, and interpretation of data, writing of the report and in the decision to submit the article for publication.",

year = "2012",

month = oct,

day = "19",

doi = "10.1016/j.febslet.2012.08.030",

language = "English",

volume = "586",

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journal = "FEBS Letters",

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AU - Chakraborty, Sandeep

AU - Asgeirsson, Bjarni

AU - Minda, Renu

AU - Salaye, Lipika

AU - Frere, Jean-Marie

AU - Rao, Basuthkar J.

N1 - Funding Information: B.J.R. would like to thank the Tata Institute of Fundamental Research (Department of Atomic Energy) and Department of Science and Technology (JC Bose Award Grant) for financial support. B.A. extends gratitude to the Icelandic National Research Council (RANNIS) and the University of Iceland Research Fund for supporting the project financially. The work in Liege was supported by an IUAP program funded by the Belgian federal government. The funders had no role in study design, collection, and interpretation of data, writing of the report and in the decision to submit the article for publication.

PY - 2012/10/19

Y1 - 2012/10/19

N2 - We demonstrate the inhibition of the native phosphatase activity of a cold active alkaline phosphatase from Vibrio (VAP) (IC50 of 44 ± 4 (n = 4) μM at pH 7.0 after a 30 min preincubation) by a specific β-lactam compound (only by imipenem, and not by ertapenem, meropenem, ampicillin or penicillin G). The homologous scaffold was detected by an in silico analysis that established the spatial and electrostatic congruence of the active site of a Class B2 CphA metallo-β-lactamase from Aeromonas hydrophila to the active site of VAP. The tested β-lactam compounds did not inhibit Escherichia coli or shrimp alkaline phosphatase, which could be ascribed to the lower congruence indicated by CLASP. There was no discernible β-lactamase activity in the tested alkaline phosphatases. This is the first time a scaffold recognizing imipenem in an alkaline phosphatase (VAP) has been demonstrated.

AB - We demonstrate the inhibition of the native phosphatase activity of a cold active alkaline phosphatase from Vibrio (VAP) (IC50 of 44 ± 4 (n = 4) μM at pH 7.0 after a 30 min preincubation) by a specific β-lactam compound (only by imipenem, and not by ertapenem, meropenem, ampicillin or penicillin G). The homologous scaffold was detected by an in silico analysis that established the spatial and electrostatic congruence of the active site of a Class B2 CphA metallo-β-lactamase from Aeromonas hydrophila to the active site of VAP. The tested β-lactam compounds did not inhibit Escherichia coli or shrimp alkaline phosphatase, which could be ascribed to the lower congruence indicated by CLASP. There was no discernible β-lactamase activity in the tested alkaline phosphatases. This is the first time a scaffold recognizing imipenem in an alkaline phosphatase (VAP) has been demonstrated.

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KW - Alkaline phosphatase

KW - Antibiotic resistance

KW - Carbapenemases

KW - Cold-active Vibrio

KW - Computational biology

KW - Finite difference Poisson-Boltzmann (FDPB)

KW - Imipenem

KW - Inhibition

KW - Metallo-betalactamase

KW - Promiscuous active site

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JO - FEBS Letters

JF - FEBS Letters

IS - 20

ER -

Inhibition of a cold-active alkaline phosphatase by imipenem revealed by in silico modeling of metallo-beta-lactamase active sites

Abstract

Bibliographical note

Other keywords

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