UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Robust prediction of resistance to trimethoprim in Staphylococcus aureus

Fowler, PW; Cole, K; Gordon, NC; Kearns, AM; Llewelyn, MJ; Peto, TEA; Crook, DW; (2018) Robust prediction of resistance to trimethoprim in Staphylococcus aureus. Cell Chemical Biology , 25 (3) 339-349.e4. 10.1016/j.chembiol.2017.12.009. Green open access

[thumbnail of dhfr-proof-10-plain.pdf]
Preview
Text
dhfr-proof-10-plain.pdf - Accepted Version

Download (4MB) | Preview

Abstract

The rise of antibiotic resistance threatens modern medicine; to combat it new diagnostic methods are required. Sequencing the whole genome of a pathogen offers the potential to accurately determine which antibiotics will be effective to treat a patient. A key limitation of this approach is that it cannot classify rare or previously unseen mutations. Here we demonstrate that alchemical free energy methods, a well-established class of methods from computational chemistry, can successfully predict whether mutations in Staphylococ-cus aureus dihydrofolate reductase confer resistance to trimethoprim. We also show that the method is quantitively accurate by calculating how much the most common resistance-conferring mutation, F99Y, reduces the binding free energy of trimethoprim and comparing predicted and experimentally-measured minimum inhibitory concentrations for seven different mutations. Finally, by considering up to 32 free energy calculations for each mutation, we estimate its specificity and sensitivity.

Type: Article
Title: Robust prediction of resistance to trimethoprim in Staphylococcus aureus
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.chembiol.2017.12.009
Publisher version: https://doi.org/10.1016/j.chembiol.2017.12.009
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: clinical microbiology, antibiotic susceptibility testing, free energy calculations, antimicrobial resistance
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10028148
Downloads since deposit
85Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item