Small but mighty: Investigate how c-di-AMP contributes to osmotic regulation, amino acid metabolism, respiration and beta-lactam resistance in Staphylococcus aureus

The signalling nucleotide c-di-AMP is intimately linked to osmotic regulation and essential for the growth of Staphylococcus aureus under standard conditions. However, the molecular mechanisms behind this are currently not understood. Osmolarity in bacteria is regulated through the intracellular levels of potassium, osmolytes and amino acids. c-di-AMP directly or indirectly regulates the uptake and synthesis of all three compounds and the mechanisms behind this will be investigated in this work. Furthermore, we have recently discovered that c-di-AMP is dispensable when S. aureus is grown under anaerobic conditions, suggesting that fundamental cellular processes that are controlled by c-di-AMP are regulated differently during anaerobic growth. Here, we will address how c-di-AMP contributes to the osmotic regulation in bacteria, how this affects their ability to cope with cell wall-targeting antibiotics and how fundamental processes such as osmolyte uptake and amino acid utilization are altered under low oxygen conditions, which S. aureus encounters during infection. As nucleotide signalling molecules have critical functions that allow bacteria to adapt rapidly to changing conditions, these studies will provide important insight into the survival of this pathogen in the environment as well as on changes occurring when it transitions to growth in a human host.