RNA quality control enables antibiotic tolerance

Antibiotic resistance poses significant challenges, yet pathogen adaptation pathways vary. To determine how host environments affect adaptation, we experimentally evolved Streptococcus pneumoniae in mice subjected to antibiotics in the context of distinct immune states. High fitness costs of canonical resistance restrict its emergence. Instead, populations adopt context-specific adaptive strategies. While neutrophil-replete environments select for immune-evasive mutations in nicotinamidase, general antibiotic stress drives convergent mutations in rny, encoding the RNA degradosome scaffold RNase Y. In contrast, antibiotic-induced death in wild-type bacteria is driven by transcriptional collapse; rny mutants avert this fate via a bet-hedging strategy, in which a resilient minority maintains a near-baseline transcriptional profile while a majority undergoes selective RNA degradation to preserve transcript fidelity. Upon stress removal, these populations execute a prioritized transcriptional ribosomal reboot, facilitating recovery. Thus, RNA turnover is a tunable master regulator of stress tolerance that pathogens exploit to survive the combined pressures of antibiotics and immunity.