Antibiotics Disrupt Coordination between Transcriptional and Phenotypic Stress Responses in Pathogenic Bacteria

Cell Rep. 2017 Aug 15;20(7):1705-1716. doi: 10.1016/j.celrep.2017.07.062.

Abstract

Bacterial genes that change in expression upon environmental disturbance have commonly been seen as those that must also phenotypically matter. However, several studies suggest that differentially expressed genes are rarely phenotypically important. We demonstrate, for Gram-positive and Gram-negative bacteria, that these seemingly uncoordinated gene sets are involved in responses that can be linked through topological network analysis. However, the level of coordination is stress dependent. While a well-coordinated response is triggered in response to nutrient stress, antibiotics trigger an uncoordinated response in which transcriptionally and phenotypically important genes are neither linked spatially nor in their magnitude. Moreover, a gene expression meta-analysis reveals that genes with large fitness changes during stress have low transcriptional variation across hundreds of other conditions, and vice versa. Our work suggests that cellular responses can be understood through network models that incorporate regulatory and genetic relationships, which could aid drug target predictions and genetic network engineering.

Keywords: Pseudomonas; RNA-seq; Streptococcus; Tn-seq; data integration; metabolic modeling; stress response; systems biology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Culture Media / chemistry
  • Culture Media / pharmacology
  • Gene Expression Profiling
  • Gene Expression Regulation, Bacterial*
  • Gene Regulatory Networks*
  • Genes, Bacterial*
  • Genetic Fitness
  • Phenotype
  • Pseudomonas aeruginosa / drug effects*
  • Pseudomonas aeruginosa / genetics
  • Pseudomonas aeruginosa / growth & development
  • Pseudomonas aeruginosa / metabolism
  • Streptococcus pneumoniae / drug effects*
  • Streptococcus pneumoniae / genetics
  • Streptococcus pneumoniae / growth & development
  • Streptococcus pneumoniae / metabolism
  • Stress, Physiological
  • Transcription, Genetic / drug effects*

Substances

  • Anti-Bacterial Agents
  • Culture Media