Extreme antagonism arising from gene-environment interactions*

Antagonistic interactions in biological systems, which occur when one perturbation blunts the effect of another, are typically interpreted as evidence that the two perturbations impact the same cellular pathway or function. Yet, this interpretation ignores extreme antagonistic interactions wherein an otherwise deleterious perturbation compensates for the function lost due to a prior perturbation. Here, we report on gene-environment (GxE) interactions involving mutations that are deleterious in a permissive environment but beneficial in a specific environment that restricts growth. These extreme antagonistic interactions constitute GxE analogs of synthetic rescues previously observed for gene-gene interactions. Our approach uses two independent adaptive evolution steps to address the lack of experimental methods to systematically identify such extreme interactions. We successively adapt Escherichia coli to defined glucose media without and with the antibiotic rifampicin, revealing multiple mutations that are beneficial in rifampicin's presence and deleterious in its absence. This work facilitates the systematic characterization of extreme antagonistic gene-drug interactions, which can be used to identify targets to select against antibiotic resistance.