C-di-AMP levels modulate <i>Staphylococcus aureus</i> cell wall thickness, response to oxidative stress, and antibiotic resistance and tolerance

Abstract

Antibiotic resistance and tolerance are substantial healthcare-related problems, hampering effective treatment of bacterial infections. Mutations in the phosphodiesterase GdpP, which degrades cyclic di-3', 5'-adenosine monophosphate (c-di-AMP), have recently been associated with resistance to beta-lactam antibiotics in clinical <i>Staphylococcus aureus</i> isolates. In this study, we show that high c-di-AMP levels decreased the cell size and increased the cell wall thickness in <i>S. aureus</i> mutant strains. As a consequence, an increase in resistance to cell wall targeting antibiotics, such as oxacillin and fosfomycin as well as in tolerance to ceftaroline, a cephalosporine used to treat methicillin-resistant <i>S. aureus</i> infections, was observed. These findings underline the importance of investigating the role of c-di-AMP in the development of tolerance and resistance to antibiotics in order to optimize treatment in the clinical setting.