The diadenosine tetraphosphate hydrolase YqeK controls fitness, biofilm formation, staphyloxanthin production and virulence in Staphylococcus aureus

Diadenosine tetraphosphate (Ap4A) is a crucial metabolite in Staphylococcus aureus, with its degradation facilitated by the YqeK hydrolase. This study delves into the roles of Ap4A in the stress response, antibiotic resistance, biofilm formation, and virulence of S. aureus COL strain. The yqeK mutant, lacking YqeK, exhibits a 105-fold higher Ap4A level, alongside reduced adenylate and guanylate nucleotide pools.

The mutant experiences diminished growth and survival in various conditions, including oxidative stress and during macrophage infection. Transcriptomic analysis uncovers upregulation of genes involved in amino acid and GTP synthesis, while AgrA, Fur, PurR, and T-box Cys regulons are downregulated. These changes can be reverted in a yqeK complemented strain, suggesting Ap4A influences the host-pathogen interaction.

Enhanced biofilm formation, increased iron levels, and reduced staphyloxanthin levels are also observed in the yqeK mutant. Infection assays reveal decreased survival of the mutant inside murine macrophages, linking Ap4A to pathogenicity regulation via Agr-controlled virulence factors. Future research must focus on understanding Ap4A's role in nucleotide, iron, and amino acid metabolism, as well as its impact on biofilm and virulence phenotypes in S. aureus.

This research provides valuable insights into potential new drug targets to combat S. aureus infections.