Noisy Response to Antibiotic Stress Predicts Subsequent Single-Cell Survival in an Acidic Environment.
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.
IST Austria, 3400 Klosterneuburg, Austria.
Karin
K
Mitosch
IST Austria, 3400 Klosterneuburg, Austria; Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92093, USA.
Georg
G
Rieckh
IST Austria, 3400 Klosterneuburg, Austria; Institute for Theoretical Physics, University of Cologne, 50937 Cologne, Germany. Electronic address: t.bollenbach@uni-koeln.de.
Tobias
T
Bollenbach
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects*; D060833:Cellular Microenvironment; D048168:Escherichia coli K12 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D017353:Gene Deletion; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D044085:Microfluidics; D009245:NADH Dehydrogenase / Q000235:genetics*; D013312:Stress, Physiological; D059008:Time-Lapse Imaging
D000900:Anti-Bacterial Agents; D009245:NADH Dehydrogenase
Escherichia coli; acid stress; antibiotics; cross-protection; microbial stress response; microfluidics; noise in gene expression; phenotypic heterogeneity; single-cell gene expression dynamics; trimethoprim