Noisy Response to Antibiotic Stress Predicts Subsequent Single-Cell Survival in an Acidic Environment

Cell Syst. 2017 Apr 26;4(4):393-403.e5. doi: 10.1016/j.cels.2017.03.001. Epub 2017 Mar 22.


Antibiotics elicit drastic changes in microbial gene expression, including the induction of stress response genes. While certain stress responses are known to "cross-protect" bacteria from other stressors, it is unclear whether cellular responses to antibiotics have a similar protective role. By measuring the genome-wide transcriptional response dynamics of Escherichia coli to four antibiotics, we found that trimethoprim induces a rapid acid stress response that protects bacteria from subsequent exposure to acid. Combining microfluidics with time-lapse imaging to monitor survival and acid stress response in single cells revealed that the noisy expression of the acid resistance operon gadBC correlates with single-cell survival. Cells with higher gadBC expression following trimethoprim maintain higher intracellular pH and survive the acid stress longer. The seemingly random single-cell survival under acid stress can therefore be predicted from gadBC expression and rationalized in terms of GadB/C molecular function. Overall, we provide a roadmap for identifying the molecular mechanisms of single-cell cross-protection between antibiotics and other stressors.

Keywords: Escherichia coli; acid stress; antibiotics; cross-protection; microbial stress response; microfluidics; noise in gene expression; phenotypic heterogeneity; single-cell gene expression dynamics; trimethoprim.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Cell Survival / drug effects*
  • Cellular Microenvironment
  • Escherichia coli K12 / drug effects*
  • Escherichia coli K12 / genetics
  • Escherichia coli K12 / physiology
  • Gene Deletion
  • Gene Expression Regulation, Bacterial / drug effects
  • Hydrogen-Ion Concentration
  • Microfluidics
  • NADH Dehydrogenase / genetics*
  • Stress, Physiological*
  • Time-Lapse Imaging


  • Anti-Bacterial Agents
  • NADH Dehydrogenase