Antibiotic resistance is a concern that challenges the advance of medical care. Staphylococcus aureus can cause a wide range of infections, both in humans and animals. The antimicrobial resistance that S. aureus can exhibit makes these infections life threatening and difficult to treat. It has been observed that when S. aureus already has a mecA gene (which encodes for PBP2A and confers low level resistance to β-lactams), mutations in the (p)ppGpp and c-di-AMP signalling nucleotides pathways confer high level antibiotic resistance. In this context, we explore the relationship between resistance and signalling nucleotides levels, diving into the different effects that the signalling nucleotides may have on the cell that lead to the observed high-level resistance phenotype.