期刊
NATURE MICROBIOLOGY
卷 2, 期 1, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nmicrobiol.2016.194
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资金
- Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA) Program under NIAID/NIH [HHSN272200700055C]
- Department of Medicine, Imperial College
- BBSRC
- Wellcome Trust
- Faculty of Medicine, Imperial College London
- Inlaks Shivdasani Foundation
- Royal Society [107660/Z/15/Z]
- Wellcome Trust [107660/Z/15/Z, 100958/Z/13/Z] Funding Source: Wellcome Trust
- Biotechnology and Biological Sciences Research Council [BB/I001492/1] Funding Source: researchfish
- Medical Research Council [MR/J006874/1B, MR/J006874/1] Funding Source: researchfish
- Wellcome Trust [100958/Z/13/Z] Funding Source: researchfish
- BBSRC [BB/I001492/1] Funding Source: UKRI
- MRC [MR/J006874/1] Funding Source: UKRI
Daptomycin is a bactericidal antibiotic of last resort for serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA)(1,2). Although resistance is rare, treatment failure can occur in more than 20% of cases(3,4) and so there is a pressing need to identify and mitigate factors that contribute to poor therapeutic outcomes. Here, we show that loss of the Agr quorum-sensing system, which frequently occurs in clinical isolates, enhances S. aureus survival during daptomycin treatment. Wild-type S. aureus was killed rapidly by daptomycin, but Agr-defective mutants survived antibiotic exposure by releasing membrane phospholipids, which bound and inactivated the antibiotic. Although wild-type bacteria also released phospholipid in response to daptomycin, Agr-triggered secretion of small cytolytic toxins, known as phenol soluble modulins, prevented antibiotic inactivation. Phospholipid shedding by S. aureus occurred via an active process and was inhibited by the beta-lactam antibiotic oxacillin, which slowed inactivation of daptomycin and enhanced bacterial killing. In conclusion, S. aureus possesses a transient defence mechanism that protects against daptomycin, which can be compromised by Agr-triggered toxin production or an existing therapeutic antibiotic.
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