Cargando…

How quickly can we predict trimethoprim resistance using alchemical free energy methods?

The emergence of antimicrobial resistance threatens modern medicine and necessitates more personalized treatment of bacterial infections. Sequencing the whole genome of the pathogen(s) in a clinical sample offers one way to improve clinical microbiology diagnostic services, and has already been adop...

Descripción completa

Detalles Bibliográficos
Autor principal: Fowler, Philip W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653339/
https://www.ncbi.nlm.nih.gov/pubmed/33178416
http://dx.doi.org/10.1098/rsfs.2019.0141
_version_ 1783607886503477248
author Fowler, Philip W.
author_facet Fowler, Philip W.
author_sort Fowler, Philip W.
collection PubMed
description The emergence of antimicrobial resistance threatens modern medicine and necessitates more personalized treatment of bacterial infections. Sequencing the whole genome of the pathogen(s) in a clinical sample offers one way to improve clinical microbiology diagnostic services, and has already been adopted for tuberculosis in some countries. A key weakness of a genetics clinical microbiology is it cannot return a result for rare or novel genetic variants and therefore predictive methods are required. Non-synonymous mutations in the S. aureus dfrB gene can be successfully classified as either conferring resistance (or not) by calculating their effect on the binding free energy of the antibiotic, trimethoprim. The underlying approach, alchemical free energy methods, requires large numbers of molecular dynamics simulations to be run. We show that a large number (N = 15) of binding free energies calculated from a series of very short (50 ps) molecular dynamics simulations are able to satisfactorily classify all seven mutations in our clinically derived testset. A result for a single mutation could therefore be returned in less than an hour, thereby demonstrating that this or similar methods are now sufficiently fast and reproducible for clinical use.
format Online
Article
Text
id pubmed-7653339
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher The Royal Society
record_format MEDLINE/PubMed
spelling pubmed-76533392020-11-10 How quickly can we predict trimethoprim resistance using alchemical free energy methods? Fowler, Philip W. Interface Focus Articles The emergence of antimicrobial resistance threatens modern medicine and necessitates more personalized treatment of bacterial infections. Sequencing the whole genome of the pathogen(s) in a clinical sample offers one way to improve clinical microbiology diagnostic services, and has already been adopted for tuberculosis in some countries. A key weakness of a genetics clinical microbiology is it cannot return a result for rare or novel genetic variants and therefore predictive methods are required. Non-synonymous mutations in the S. aureus dfrB gene can be successfully classified as either conferring resistance (or not) by calculating their effect on the binding free energy of the antibiotic, trimethoprim. The underlying approach, alchemical free energy methods, requires large numbers of molecular dynamics simulations to be run. We show that a large number (N = 15) of binding free energies calculated from a series of very short (50 ps) molecular dynamics simulations are able to satisfactorily classify all seven mutations in our clinically derived testset. A result for a single mutation could therefore be returned in less than an hour, thereby demonstrating that this or similar methods are now sufficiently fast and reproducible for clinical use. The Royal Society 2020-12-06 2020-10-16 /pmc/articles/PMC7653339/ /pubmed/33178416 http://dx.doi.org/10.1098/rsfs.2019.0141 Text en © 2020 The Authors. http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/http://creativecommons.org/licenses/by/4.0/Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.
spellingShingle Articles
Fowler, Philip W.
How quickly can we predict trimethoprim resistance using alchemical free energy methods?
title How quickly can we predict trimethoprim resistance using alchemical free energy methods?
title_full How quickly can we predict trimethoprim resistance using alchemical free energy methods?
title_fullStr How quickly can we predict trimethoprim resistance using alchemical free energy methods?
title_full_unstemmed How quickly can we predict trimethoprim resistance using alchemical free energy methods?
title_short How quickly can we predict trimethoprim resistance using alchemical free energy methods?
title_sort how quickly can we predict trimethoprim resistance using alchemical free energy methods?
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653339/
https://www.ncbi.nlm.nih.gov/pubmed/33178416
http://dx.doi.org/10.1098/rsfs.2019.0141
work_keys_str_mv AT fowlerphilipw howquicklycanwepredicttrimethoprimresistanceusingalchemicalfreeenergymethods