期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 66, 期 2, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01431-21
关键词
GdpP; Staphylococcus aureus; beta-lactams; cyclic-di-AMP; tolerance
资金
- NIH [2R01AI100291, R21AI142501]
- University Systems of Maryland
Infections caused by Staphylococcus aureus are a leading cause of mortality. Resistance to traditional antibiotics, including beta-lactams, makes treating these infections difficult. Mutations in the gdpP gene have been found to increase antibiotic tolerance and promote the development of beta-lactam resistance in S. aureus.
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 beta-lactams. We previously reported the presence of mutations in gdpP among S. aureus strains that were obtained by serial passaging in beta-lactam drugs. Similar mutations have recently been reported in natural S. aureus isolates that are either nonsusceptible or resistant to beta-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 beta-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 beta-lactam challenge (2 to 3 log increase in bacterial CFU) by promoting tolerance without enhancing MICs of beta-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 beta-lactam resistance. Loss of GdpP function thus increases tolerance to beta-lactams that can lead to its therapy failure and can permit beta-lactam resistance to occur more readily.
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