Epistasis decreases with increasing antibiotic pressure but not temperature

Abstract

Predicting mutational effects is essential for the control of antibiotic resistance (ABR). Predictions are difficult when there are strong genotype-by-environment (GxE), gene-by-gene (GxG or epistatic), or gene- by-gene-by-environment (GxGxE) interactions. We quantified GxGxE effects in Escherichia coli across environmental gradients. We created intergenic fitness landscapes using gene knock-outs and single nucleotide ABR mutations previously identified to vary in the extent of GxE effects in our environments of interest. Then, we measured competitive fitness across a complete combinatorial set of temperature and antibiotic dosage gradients. In this way, we assessed the predictability of 15 fitness landscapes across 12 different but related environments. We found GxG interactions and rugged fitness landscapes in the absence of antibiotic, but as antibiotic concentration increased, the fitness effects of ABR genotypes quickly overshadowed those of gene knock-outs, and the landscapes became smoother. Our work reiterates that some single mutants, like those conferring resistance or susceptibility to antibiotics, have consistent effects across genetic backgrounds in stressful environments. Thus, although epistasis may reduce the predictability of evolution in benign environments, evolution may be more predictable in adverse environments.