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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 β-lactams. We previously reported the presence of mutations in gdpP among S. aureus strains that were obtained by serial passaging in β-lactam drugs. Similar mutations have recently been reported in natural S. aureus isolates that are either nonsusceptible or resistant to β-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 β-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 β-lactam challenge (2 to 3 log increase in bacterial CFU) by promoting tolerance without enhancing MICs of β-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 β-lactam resistance. Loss of GdpP function thus increases tolerance to β-lactams that can lead to its therapy failure and can permit β-lactam resistance to occur more readily.


Raymond Poon, Li Basuino, Nidhi Satishkumar, Aditi Chatterjee, Nagaraja Mukkayyan, Emma Buggeln, Liusheng Huang, Vinod Nair, Maria A Argudín, Sandip K Datta, Henry F Chambers, Som S Chatterjee. Loss of GdpP Function in Staphylococcus aureus Leads to β-Lactam Tolerance and Enhanced Evolution of β-Lactam Resistance. Antimicrobial agents and chemotherapy. 2022 Feb 15;66(2):e0143121

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PMID: 34843389

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