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Multiscale Simulations of Clavulanate Inhibition Identify the Reactive Complex in Class A β-Lactamases and Predict the Efficiency of Inhibition
| Indexado |
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| DOI | 10.1021/ACS.BIOCHEM.8B00480 | ||||
| Año | 2018 | ||||
| Tipo | artículo de investigación |
Citas Totales
Autores Afiliación Chile
Instituciones Chile
% Participación
Internacional
Autores
Afiliación Extranjera
Instituciones
Extranjeras
Abstract
Clavulanate is used as an effective drug in combination with beta-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 beta-lactamases KPC-2 and TEM-1. Simulations of the deacylation reactions identify the decarboxylated transenamine complex as being responsible for inhibition. Further, the obtained free energy barriers discriminate clinically relevant inhibition (TEM-l) from less effective inhibition (KPC-2).
| Ord. | Autor | Género | Institución - País |
|---|---|---|---|
| 1 | Fritz, Ruben Alejandro | Hombre |
Universidad de Talca - Chile
|
| 2 | ALZATE-MORALES, JANS HUMBERTO | - |
Universidad de Talca - Chile
|
| 3 | Spencer, James | Hombre |
Univ Bristol - Reino Unido
University of Bristol - Reino Unido |
| 4 | Mulholland, Adrian J. | Hombre |
Univ Bristol - Reino Unido
University of Bristol - Reino Unido |
| 5 | van der Kamp, Marc W. | Hombre |
Univ Bristol - Reino Unido
University of Bristol - Reino Unido |
| Fuente |
|---|
| FONDECYT |
| University of Talca |
| Biotechnology and Biological Sciences Research Council |
| Universidad de Talca |
| EPSRC |
| Engineering and Physical Sciences Research Council |
| Royal Society of Chemistry (RSC) |
| Royal Society of Chemistry |
| Agradecimiento |
|---|
| R.A.F. thanks the Royal Society of Chemistry (RSC) for the Researcher Mobility Grant awarded in 2016 and the University of Talca for a Ph.D. scholarship. R.A.F. and J.H.A.-M. acknowledge the financial support through Project FONDECYT 1140618. A.J.M. thanks the EPSRC for support (EP/M027546/1 and EP/022609/1). M.W.v.d.K. is a BBSRC David Phillips Fellow (BB/M026280/1). |
| *E-mail: jalzate@utalca.cl. *E-mail: adrian.mulholland@bristol.ac.uk. *E-mail: marc.vanderkamp@bristol.ac.uk. ORCID Rubeń A. Fritz: 0000-0002-6691-4740 James Spencer: 0000-0002-4602-0571 Marc W. van der Kamp: 0000-0002-8060-3359 Author Contributions M.W.v.d.K. and A.J.M. designed the study, and R.A.F. performed and analyzed all simulations, with help from M.W.v.d.K. All authors contributed to writing the manuscript. Funding R.A.F. thanks the Royal Society of Chemistry (RSC) for the Researcher Mobility Grant awarded in 2016 and the University of Talca for a Ph.D. scholarship. R.A.F. and J.H.A.-M. acknowledge the financial support through Project FONDE-CYT 1140618. A.J.M. thanks the EPSRC for support (EP/ M027546/1 and EP/022609/1). M.W.v.d.K. is a BBSRC David Phillips Fellow (BB/M026280/1). Notes The authors declare no competing financial interest. |
