Dengler Haunreiter, Vanina; https://orcid.org/0000-0002-0850-0363, Tarnutzer, Andrea; https://orcid.org/0000-0003-2952-6287, Bär, Julian; https://orcid.org/0000-0003-1929-0338, von Matt, Manuela, Hertegonne, Sanne; https://orcid.org/0000-0003-1655-203X, Andreoni, Federica, Vulin, Clément; https://orcid.org/0000-0003-3914-0708, Künzi, Lisa, Menzi, Carmen, Kiefer, Patrick, Christen, Philipp, Vorholt, Julia A; https://orcid.org/0000-0002-6011-4910, Zinkernagel, Annelies S; https://orcid.org/0000-0003-4700-1118, Dengler Haunreiter, Vanina; https://orcid.org/0000-0002-0850-0363, Tarnutzer, Andrea; https://orcid.org/0000-0003-2952-6287, Bär, Julian; https://orcid.org/0000-0003-1929-0338, von Matt, Manuela, Hertegonne, Sanne; https://orcid.org/0000-0003-1655-203X, Andreoni, Federica, Vulin, Clément; https://orcid.org/0000-0003-3914-0708, Künzi, Lisa, Menzi, Carmen, Kiefer, Patrick, Christen, Philipp, Vorholt, Julia A; https://orcid.org/0000-0002-6011-4910, and Zinkernagel, Annelies S; https://orcid.org/0000-0003-4700-1118
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 Staphylococcus aureus isolates. In this study, we show that high c-di-AMP levels decreased the cell size and increased the cell wall thickness in S. aureus 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 S. aureus 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.