A Delicate Connection: c-di-AMP Affects Cell Integrity by Controlling Osmolyte Transport

Trends Microbiol. 2018 Mar;26(3):175-185. doi: 10.1016/j.tim.2017.09.003. Epub 2017 Sep 28.


Bacteria use second-messenger molecules to adapt to their environment. Several second messengers, among them cyclic di-AMP (c-di-AMP), have been discovered and intensively studied. Interestingly, c-di-AMP is essential for growth of Gram-positive bacteria such as Bacillus subtilis, Listeria monocytogenes, and Staphylococcus aureus. Many studies demonstrated that perturbation of c-di-AMP metabolism affects the integrity of the bacterial cell envelope. Therefore, it has been assumed that the nucleotide is essential for proper cell envelope synthesis. In this Opinion paper, we propose that the cell envelope phenotypes caused by perturbations of c-di-AMP metabolism can be interpreted differently: c-di-AMP might indirectly control cell envelope integrity by modulating the turgor, a physical variable that needs to be tightly adjusted. We also discuss open questions related to c-di-AMP metabolism that need to be urgently addressed by future studies.

Keywords: Bacillus subtilis; Listeria monocytogenes; Staphylococcus aureus; cell wall; cyclic di-AMP; osmoprotection; potassium homeostasis; turgor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Bacillus subtilis / metabolism
  • Bacterial Proteins
  • Cell Membrane / metabolism*
  • Cell Wall / metabolism
  • Cyclic AMP / metabolism*
  • Gram-Positive Bacteria / metabolism*
  • Listeria monocytogenes / metabolism
  • Membrane Transport Proteins / metabolism*
  • Osmoregulation / physiology*
  • Phenotype
  • Second Messenger Systems
  • Staphylococcus aureus / metabolism


  • Bacterial Proteins
  • Membrane Transport Proteins
  • Cyclic AMP