  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 interactions
involving genetic mutations that are deleterious in a permissive environment
but beneficial in a specific environment that restricts growth. These extreme
antagonistic interactions constitute gene-environment 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 apply the
approach to Escherichia coli by successively adapting it to defined glucose
media without and with the antibiotic rifampicin. The approach identified
multiple mutations that are beneficial in the presence of rifampicin and
deleterious in its absence. The analysis of transcription shows that the
antagonistic adaptive mutations repress a stringent response-like
transcriptional program, while non-antagonistic mutations have an opposite
transcriptional profile. Our approach represents a step toward the systematic
characterization of extreme antagonistic gene-drug interactions, which can be
used to identify targets to select against antibiotic resistance.
