Loss of GdpP Function in Staphylococcus aureus Leads to ß-Lactam Tolerance and Enhanced Evolution of ß-Lactam Resistance.

Infections caused by Staphylococcus aureus are a leading cause of mortality. Treating infections caused by S. aureus is difficult due to resistance against most traditional antibiotics, including ß-lactams. We previously reported the presence of mutations in gdpP among S. aureus strains that were obtained by serial passaging in ß-lactam drugs. Similar mutations have recently been reported in natural S. aureus isolates that are either nonsusceptible or resistant to ß-lactam antibiotics. gdpP codes for a phosphodiesterase that cleaves cyclic-di-AMP (CDA), a newly discovered second messenger. In this study, we sought to identify the role of gdpP in ß-lactam resistance in S. aureus. Our results showed that gdpP-associated mutations caused 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 ß-lactam challenge (2 to 3 log increase in bacterial CFU) by promoting tolerance without enhancing MICs of ß-lactam antibiotics. Our results demonstrated that increased drug tolerance due to loss of GdpP function can provide a selective advantage in acquisition of high-level ß-lactam resistance. Loss of GdpP function thus increases tolerance to ß-lactams that can lead to its therapy failure and can permit ß-lactam resistance to occur more readily.