Biophysical principles predict fitness landscapes of drug resistance
Abstract
Development of predictive models of antibiotic resistance is challenging due to a lack of understanding of the relationship between molecular and fitness effects of mutations (the genotype-phenotype gap). Here we close the genotype-phenotype gap for an essential enzyme, dihydrofolate reductase (DHFR), which is an important target of the common antibiotic trimethoprim. We show that IC50 of trimethoprim resistance of Escherichia coli can be predicted, with high accuracy, from a unique combination of molecular properties of stepwise-resistant DHFR variants. These results show that the challenge to predict de novo evolutionary dynamics of antibiotic resistance lies in the need for accurate prediction of the effects of mutations on the molecular properties of target enzymes.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- March 2016
- DOI:
- 10.1073/pnas.1601441113
- Bibcode:
- 2016PNAS..113E1470R