Literature DB >> 29812917

Multiscale Simulations of Clavulanate Inhibition Identify the Reactive Complex in Class A β-Lactamases and Predict the Efficiency of Inhibition.

Rubén A Fritz1, Jans H Alzate-Morales1, James Spencer2, Adrian J Mulholland3, Marc W van der Kamp3,4.   

Abstract

Clavulanate is used as an effective drug in combination with β-lactam antibiotics to treat infections of some antibiotic resistant bacteria. Here, we perform combined quantum mechanics/molecular mechanics simulations of several covalent complexes of clavulanate with class A β-lactamases KPC-2 and TEM-1. Simulations of the deacylation reactions identify the decarboxylated trans-enamine complex as being responsible for inhibition. Further, the obtained free energy barriers discriminate clinically relevant inhibition (TEM-1) from less effective inhibition (KPC-2).

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Year:  2018        PMID： 29812917     DOI： 10.1021/acs.biochem.8b00480

Source DB:  PubMed          Journal:  Biochemistry        ISSN： 0006-2960            Impact factor:   3.162


  7 in total

1.  A multiscale approach to predict the binding mode of metallo beta-lactamase inhibitors.

Authors:  Silvia Gervasoni; James Spencer; Philip Hinchliffe; Alessandro Pedretti; Franco Vairoletti; Graciela Mahler; Adrian J Mulholland
Journal:  Proteins       Date:  2021-09-20

Review 2.  Predicting allostery and microbial drug resistance with molecular simulations.

Authors:  George A Cortina; Peter M Kasson
Journal:  Curr Opin Struct Biol       Date:  2018-09-19       Impact factor: 6.809

3.  Molecular Bases of the Membrane Association Mechanism Potentiating Antibiotic Resistance by New Delhi Metallo-β-lactamase 1.

Authors:  Alessio Prunotto; Guillermo Bahr; Lisandro J González; Alejandro J Vila; Matteo Dal Peraro
Journal:  ACS Infect Dis       Date:  2020-09-14       Impact factor: 5.578

4.  Allosteric communication in class A β-lactamases occurs via cooperative coupling of loop dynamics.

Authors:  Ioannis Galdadas; Shen Qu; Ana Sofia F Oliveira; Edgar Olehnovics; Andrew R Mack; Maria F Mojica; Pratul K Agarwal; Catherine L Tooke; Francesco Luigi Gervasio; James Spencer; Robert A Bonomo; Adrian J Mulholland; Shozeb Haider
Journal:  Elife       Date:  2021-03-23       Impact factor: 8.140

5.  Mechanistic Insights into Enzyme Catalysis from Explaining Machine-Learned Quantum Mechanical and Molecular Mechanical Minimum Energy Pathways.

Authors:  Zilin Song; Francesco Trozzi; Hao Tian; Chao Yin; Peng Tao
Journal:  ACS Phys Chem Au       Date:  2022-05-18

6.  Molecular Basis of Class A β-Lactamase Inhibition by Relebactam.

Authors:  Catherine L Tooke; Philip Hinchliffe; Pauline A Lang; Adrian J Mulholland; Jürgen Brem; Christopher J Schofield; James Spencer
Journal:  Antimicrob Agents Chemother       Date:  2019-09-23       Impact factor: 5.938

Review 7.  Dynamical nonequilibrium molecular dynamics reveals the structural basis for allostery and signal propagation in biomolecular systems.

Authors:  A Sofia F Oliveira; Giovanni Ciccotti; Shozeb Haider; Adrian J Mulholland
Journal:  Eur Phys J B       Date:  2021-07-20       Impact factor: 1.500
  7 in total

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