Environmental selection and epistasis in an empirical phenotype–environment–fitness landscape

Fitness landscapes, mappings of genotype/phenotype to their effects on fitness, are invaluable concepts in evolutionary biochemistry. Although widely discussed, measurements of phenotype–fitness landscapes in proteins remain scarce. Here, we quantify all single mutational effects on fitness and phenotype (EC50) of VIM-2 β-lactamase across a 64-fold range of ampicillin concentrations. We then construct a phenotype–fitness landscape that takes variations in environmental selection pressure into account. We found that a simple, empirical landscape accurately models the ~39,000 mutational data points, suggesting that the evolution of VIM-2 can be predicted on the basis of the selection environment. Our landscape provides new quantitative knowledge on the evolution of the β-lactamases and proteins in general, particularly their evolutionary dynamics under subinhibitory antibiotic concentrations, as well as the mechanisms and environmental dependence of non-specific epistasis. Constructing a fitness landscape from the fitness of Escherichia coli carrying single point mutants in VIM-2 β-lactamase across environments with different ampicillin concentrations and the antibiotic resistance of each variant, the authors show that the evolution of β-lactamases can be predicted based on the selection pressure in the environment.