A trade-off between stress resistance and tolerance underlies the adaptive response to hydrogen peroxide

Summary The physiological adaptation to environmental stress involves complex molecular responses leading to separate cellular fates aimed at maximizing fitness: either cells can maintain proliferation by degrading the effects of the stressor (i.e. resistance), or they focus on ensuring cell survival (i.e. tolerance), even at the expense of proliferation. These strategies are complementary, yet whether they are coordinated to ensure an optimal physiological stress response remains unknown. Here, we used microfluidics and live cell imaging to explore the genetic basis of the interplay between resistance and tolerance during the response to hydrogen peroxide (H 2 O 2 ) in budding yeast. Our analysis unraveled that the deletion of zwf1 Δ, which is responsible for NADPH synthesis via the PPP pathway, led to a decrease in resistance that was counterbalanced by an unexpected exacerbation of tolerance to H 2 O 2 . This trade-off between stress resistance and stress tolerance was further characterized using both genetic and environmental interventions, and we confirmed that it was conserved in bacteria. Our results support a model in which redox signaling triggers the switch to a nutrients-dependent non-proliferative tolerant state via inhibition of protein kinase A when the H 2 O 2 homeostatic response is overwhelmed. Our framework could help develop synergistic therapies that target mechanisms driving both resistance and tolerance to prevent drug escape mechanisms and disease relapse.