RNA Quality Control Enables Antibiotic Tolerance

By experimentally evolving Streptococcus pneumoniae in mice subjected to various antibiotics and immune states, we demonstrate that the high fitness costs of canonical resistance mutations severely restrict their emergence in vivo.

Instead, populations adopt distinct adaptive strategies depending on the specific selective context: while neutrophil-replete environments select for immune-evasive, loss-of-function mutations in the nicotinamidase SP_1583, general antibiotic stress drives convergent mutations in rny, encoding the RNA degradosome scaffold RNase Y. Isogenic rny mutants exhibit broad-spectrum tolerance and accelerated recovery. Single-cell transcriptomics reveals that antibiotic-induced death in wild-type bacteria is driven by transcriptional collapse, a lethal surge of uncontrolled transcription followed by a catastrophic loss of RNA quantity and integrity.