Antibiotic Persistence Emerges from Cell-State-Driven Transcriptional Reprogramming
Antibiotic persistence enables some bacterial cells to survive antibiotic treatment without resistance mutations, contributing to treatment failure and recurrence. The molecular basis of persistence remains unclear due to its transient and heterogeneous nature, which is obscured in bulk analyses. Here, we use bacterial single-cell RNA sequencing and survival assays to study antibiotic-induced persistence in Klebsiella pneumoniae. We find that even genetically identical cells in the same growth phase can follow distinct transcriptional trajectories leading to survival, influenced by initial cell states and antibiotic mechanisms. Genetic (rpoS deletion) and environmental changes shift these cell states and persistence levels. Our results suggest that persistence arises from cell-state-dependent transcriptional plasticity, not fixed genetic programs, highlighting new strategies to address antibiotic persistence by targeting bacterial cell states.