An Efficient Computational Assay for β-Lactam Antibiotic Breakdown by Class A β-Lactamases

Viivi Hirvonen; Katharine Hammond; Ewa Chudyk; Michael Limb; James Spencer; Adrian Mulholland; Marc Van der Kamp

doi:10.1021/acs.jcim.9b00442

An Efficient Computational Assay for β-Lactam Antibiotic Breakdown by Class A β-Lactamases

Viivi Hirvonen
, Katharine Hammond
, Ewa Chudyk
, Michael Limb
, James Spencer
, Adrian Mulholland
, Marc Van der Kamp

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

20 Citations (Scopus)

402 Downloads (Pure)

Abstract

Class A β-lactamases cause clinically relevant resistance to β-lactam antibiotics. Carbapenem degradation is a particular concern. We present an efficient QM/MM molecular simulation protocol that accurately predicts the activity of β-lactamases against carbapenems. Simulations take less than 24 CPU hours, a greater than 99% reduction, and do not require fitting against experimental data or significant parametrization. This computational assay also reveals mechanistic details of β-lactam breakdown and should assist in evaluating emerging β-lactamase variants and developing new antibiotics.

Original language	English
Pages (from-to)	3365-3369
Number of pages	5
Journal	Journal of Chemical Information and Modeling
Volume	59
Issue number	8
Early online date	30 Jul 2019
DOIs	https://doi.org/10.1021/acs.jcim.9b00442
Publication status	E-pub ahead of print - 30 Jul 2019

Research Groups and Themes

Physical & Theoretical

Access to Document

10.1021/acs.jcim.9b00442

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Persistent link

Link account to CHEM RB1768 (EP/M027546/1) - BristolBridge: Sustained chlorhexidine delivery gels for care of the umbilical cord in developing countries
Barbour , M. E. (Principal Investigator)
1/11/15 → 31/01/16
Project: Research
CCP-BioSim: Biomolecular Simulation at the Life Sciences Interface
Mulholland, A. J. (Principal Investigator)
1/07/15 → 30/04/21
Project: Research
Computational tools for enzyme engineering: bridging the gap between enzymologists and expert simulation
Mulholland, A. J. (Principal Investigator)
15/07/14 → 15/06/16
Project: Research

Insights into antibiotic inactivation by β-lactamases from multiscale simulations
Hirvonen, V. H. A. (Author), Van der Kamp, M. (Supervisor) & Spencer, J. (Supervisor), 28 Sept 2021
Student thesis: Doctoral Thesis › Doctor of Philosophy (PhD)

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HPC (High Performance Computing) and HTC (High Throughput Computing) Facilities
Alam, S. R. (Manager), Williams, D. A. G. (Manager), Eccleston, P. E. (Manager) & Greene, D. (Manager)
Facility/equipment: Facility

Cite this

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title = "An Efficient Computational Assay for β-Lactam Antibiotic Breakdown by Class A β-Lactamases",

abstract = "Class A β-lactamases cause clinically relevant resistance to β-lactam antibiotics. Carbapenem degradation is a particular concern. We present an efficient QM/MM molecular simulation protocol that accurately predicts the activity of β-lactamases against carbapenems. Simulations take less than 24 CPU hours, a greater than 99\% reduction, and do not require fitting against experimental data or significant parametrization. This computational assay also reveals mechanistic details of β-lactam breakdown and should assist in evaluating emerging β-lactamase variants and developing new antibiotics.",

author = "Viivi Hirvonen and Katharine Hammond and Ewa Chudyk and Michael Limb and James Spencer and Adrian Mulholland and \{Van der Kamp\}, Marc",

year = "2019",

month = jul,

day = "30",

doi = "10.1021/acs.jcim.9b00442",

language = "English",

volume = "59",

pages = "3365--3369",

journal = "Journal of Chemical Information and Modeling",

issn = "1549-9596",

publisher = "American Chemical Society",

number = "8",

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TY - JOUR

T1 - An Efficient Computational Assay for β-Lactam Antibiotic Breakdown by Class A β-Lactamases

AU - Hirvonen, Viivi

AU - Hammond, Katharine

AU - Chudyk, Ewa

AU - Limb, Michael

AU - Spencer, James

AU - Mulholland, Adrian

AU - Van der Kamp, Marc

PY - 2019/7/30

Y1 - 2019/7/30

N2 - Class A β-lactamases cause clinically relevant resistance to β-lactam antibiotics. Carbapenem degradation is a particular concern. We present an efficient QM/MM molecular simulation protocol that accurately predicts the activity of β-lactamases against carbapenems. Simulations take less than 24 CPU hours, a greater than 99% reduction, and do not require fitting against experimental data or significant parametrization. This computational assay also reveals mechanistic details of β-lactam breakdown and should assist in evaluating emerging β-lactamase variants and developing new antibiotics.

AB - Class A β-lactamases cause clinically relevant resistance to β-lactam antibiotics. Carbapenem degradation is a particular concern. We present an efficient QM/MM molecular simulation protocol that accurately predicts the activity of β-lactamases against carbapenems. Simulations take less than 24 CPU hours, a greater than 99% reduction, and do not require fitting against experimental data or significant parametrization. This computational assay also reveals mechanistic details of β-lactam breakdown and should assist in evaluating emerging β-lactamase variants and developing new antibiotics.

U2 - 10.1021/acs.jcim.9b00442

DO - 10.1021/acs.jcim.9b00442

M3 - Article (Academic Journal)

C2 - 31361944

SN - 1549-9596

VL - 59

SP - 3365

EP - 3369

JO - Journal of Chemical Information and Modeling

JF - Journal of Chemical Information and Modeling

IS - 8

ER -

An Efficient Computational Assay for β-Lactam Antibiotic Breakdown by Class A β-Lactamases

Abstract

Research Groups and Themes

Access to Document

Handle.net

Fingerprint

Projects

Link account to CHEM RB1768 (EP/M027546/1) - BristolBridge: Sustained chlorhexidine delivery gels for care of the umbilical cord in developing countries

CCP-BioSim: Biomolecular Simulation at the Life Sciences Interface

Computational tools for enzyme engineering: bridging the gap between enzymologists and expert simulation

Student theses

Insights into antibiotic inactivation by β-lactamases from multiscale simulations

Equipment

HPC (High Performance Computing) and HTC (High Throughput Computing) Facilities

Cite this