Loss of GdpP function in Staphylococcus aureus leads to β-lactam tolerance and enhanced evolution of β-lactam resistance

Synopsis Background We previously reported the presence of mutations in gdpP among Staphylococcus aureus strains that were obtained by serial passaging in β-lactam drugs. gdpP codes for a phosphodiesterase that cleaves cyclic-di-AMP (CDA), a newly discovered second messenger. Objectives We sought to identify the role of gdpP in β-lactam resistance of S. aureus . Methods CDA concentrations in bacterial cytosol were measured through mass-spectrometric analysis. gdpP deletion mutagenesis and their complemented strains were created in clinically relevant S. aureus strains to characterize its function. Results gdpP associated mutations among passaged strains were identified to cause loss of phosphodiesterase function, leading to increased CDA accumulation in the bacterial cytosol. Deletion of gdpP led to an enhanced ability of the bacteria to withstand a β-lactam challenge (two to three log increase in bacterial colony forming units) by promoting tolerance without enhancing MICs of β-lactam antibiotics. Our results demonstrate that increased drug tolerance due to loss of GdpP function can provide a selective advantage in acquisition of high-level β-lactam resistance and could lead to β-lactam treatment failure of S. aureus infections. Conclusions Loss of GdpP function increases tolerance to β-lactams that can lead to its therapy failure and can permit β-lactam resistance to occur more readily.