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<p>Bacteria can survive antibiotic treatment through phenotypic adaptation, a process that is often transient and involves heterogeneous transcriptional reprogramming. However, how this transcriptional heterogeneity is generated and how it influences antibiotic survival remains unclear. Here, we use bacterial single-cell RNA sequencing and functional assays in <i>Klebsiella pneumoniae</i> to characterize transcriptional heterogeneity and examine how pre-treatment cell states are associated with antibiotic-induced responses and survival outcomes. Using growth phase as a biologically meaningful axis of transcriptional variation, we reveal that even within an isogenic population, distinct transcriptional responses can be induced and co-contribute to survival. These responses are shaped by the cell’s pre-treatment transcriptional state and the mechanism of antibiotic action. Genetic and environmental perturbations, such as <i>rpoS</i> deletion and nutrient supplementation, shift pre-treatment cell states and alter survival frequencies. Our findings establish the biological significance of transcriptional heterogeneity shaped by pre-treatment cell states, providing a systems-level framework for understanding bacterial antibiotic response and suggesting strategies to enhance antibiotic efficacy by modulating cell states.</p>

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Pre-treatment bacterial cell states shape antibiotic-induced transcriptional reprogramming and survival

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月2日

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  • Qiang Liu,
  • Zehui Yu,
  • Xiaoli Liu,
  • Amy Iverson,
  • Tyler Simmons,
  • Jason W. Rosch,
  • Peijun Ma

摘要

Bacteria can survive antibiotic treatment through phenotypic adaptation, a process that is often transient and involves heterogeneous transcriptional reprogramming. However, how this transcriptional heterogeneity is generated and how it influences antibiotic survival remains unclear. Here, we use bacterial single-cell RNA sequencing and functional assays in Klebsiella pneumoniae to characterize transcriptional heterogeneity and examine how pre-treatment cell states are associated with antibiotic-induced responses and survival outcomes. Using growth phase as a biologically meaningful axis of transcriptional variation, we reveal that even within an isogenic population, distinct transcriptional responses can be induced and co-contribute to survival. These responses are shaped by the cell’s pre-treatment transcriptional state and the mechanism of antibiotic action. Genetic and environmental perturbations, such as rpoS deletion and nutrient supplementation, shift pre-treatment cell states and alter survival frequencies. Our findings establish the biological significance of transcriptional heterogeneity shaped by pre-treatment cell states, providing a systems-level framework for understanding bacterial antibiotic response and suggesting strategies to enhance antibiotic efficacy by modulating cell states.