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.
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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 |
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