Abstract Cells employ two different defense strategies against environmental stress: resistance, aimed at preserving cell proliferation by degrading the stressor, and tolerance, focused on ensuring cell survival, 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, among antioxidants, some were clearly associated with resistance while others contribute to tolerance. Furthermore, we found that the zwf1 Δ mutant, responsible for NADPH synthesis via the PPP pathway, exhibited a decrease in resistance that was counterbalanced by an unexpected exacerbation of tolerance to H 2 O 2 , thus revealing a trade-off that we further observed in E. coli . 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 both resistance and tolerance mechanisms to prevent drug-escape mechanisms and disease relapse.

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