Multiscale simulations of clavulanate inhibition identify the reactive complex in class A β-lactamases and predict efficiency of inhibition

Ruben Fritz; Jans H. Alzate-Morales; James Spencer; Adrian J. Mulholland; Marc W. Van Der Kamp

doi:10.1021/acs.biochem.8b00480

Multiscale simulations of clavulanate inhibition identify the reactive complex in class A β-lactamases and predict efficiency of inhibition

Ruben Fritz, Jans H. Alzate-Morales, James Spencer, Adrian J. Mulholland, Marc W. Van Der Kamp

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

Clavulanate is used as an effective drug in combina-tion with β-lactam antibiotics to treat infections of some antibiotic resistant bacteria. Here, we per-form combined quantum mechanics / molecular mechanics simulations of several covalent com-plexes of clavulanate with class A β-lactamases KPC-2 and TEM-1. Simulations of the deacylation reactions identify the decarboxylated trans-enamine complex as responsible for inhibition. Further, the simulations correctly discriminate between enzymes that are effectively inhibited (TEM-1) from those that are not (KPC-2) providing a 'computational assay' for clinically relevant inhibition.

Original language	English
Number of pages	4
Journal	Biochemistry
Early online date	29 May 2018
DOIs	https://doi.org/10.1021/acs.biochem.8b00480
Publication status	E-pub ahead of print - 29 May 2018

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title = "Multiscale simulations of clavulanate inhibition identify the reactive complex in class A β-lactamases and predict efficiency of inhibition",

abstract = "Clavulanate is used as an effective drug in combina-tion with β-lactam antibiotics to treat infections of some antibiotic resistant bacteria. Here, we per-form combined quantum mechanics / molecular mechanics simulations of several covalent com-plexes of clavulanate with class A β-lactamases KPC-2 and TEM-1. Simulations of the deacylation reactions identify the decarboxylated trans-enamine complex as responsible for inhibition. Further, the simulations correctly discriminate between enzymes that are effectively inhibited (TEM-1) from those that are not (KPC-2) providing a 'computational assay' for clinically relevant inhibition.",

author = "Ruben Fritz and Alzate-Morales, {Jans H.} and James Spencer and Mulholland, {Adrian J.} and {Van Der Kamp}, {Marc W.}",

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AU - Fritz, Ruben

AU - Alzate-Morales, Jans H.

AU - Spencer, James

AU - Mulholland, Adrian J.

AU - Van Der Kamp, Marc W.

PY - 2018/5/29

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N2 - Clavulanate is used as an effective drug in combina-tion with β-lactam antibiotics to treat infections of some antibiotic resistant bacteria. Here, we per-form combined quantum mechanics / molecular mechanics simulations of several covalent com-plexes of clavulanate with class A β-lactamases KPC-2 and TEM-1. Simulations of the deacylation reactions identify the decarboxylated trans-enamine complex as responsible for inhibition. Further, the simulations correctly discriminate between enzymes that are effectively inhibited (TEM-1) from those that are not (KPC-2) providing a 'computational assay' for clinically relevant inhibition.

AB - Clavulanate is used as an effective drug in combina-tion with β-lactam antibiotics to treat infections of some antibiotic resistant bacteria. Here, we per-form combined quantum mechanics / molecular mechanics simulations of several covalent com-plexes of clavulanate with class A β-lactamases KPC-2 and TEM-1. Simulations of the deacylation reactions identify the decarboxylated trans-enamine complex as responsible for inhibition. Further, the simulations correctly discriminate between enzymes that are effectively inhibited (TEM-1) from those that are not (KPC-2) providing a 'computational assay' for clinically relevant inhibition.

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JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

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Multiscale simulations of clavulanate inhibition identify the reactive complex in class A β-lactamases and predict efficiency of inhibition

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Multi-scale enzyme modelling for SynBio: optimizing biocatalysts for selective synthesis of bioactive compounds

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Multiscale simulations of clavulanate inhibition identify the reactive complex in class A β-lactamases and predict efficiency of inhibition

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Link account to CHEM RB1768 (EP/M027546/1) - Bristolbridge-Nanospears

Multi-scale enzyme modelling for SynBio: optimizing biocatalysts for selective synthesis of bioactive compounds

CCP-BioSim: Biomolecular Simulation at the Life Sciences Interface

Cite this