气候变化领域集成服务门户(CCPortal): Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success

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DOI	10.1073/pnas.2014920118
	Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success
	Huemer M.; Shambat S.M.; Bergada-Pijuan J.; Söderholm S.; Boumasmoud M.; Vulin C.; Gómez-Mejia A.; Varela M.A.; Tripathi V.; Götschi S.; Maggio E.M.; Hasse B.; Brugger S.D.; Bumann D.; Schuepbach R.A.; Zinkernagel A.S.
发表日期	2021
ISSN	00278424
卷号	118 期号:7
英文摘要	Staphylococcus aureus causes invasive infections and easily acquires antibiotic resistance. Even antibiotic-susceptible S. aureus can survive antibiotic therapy and persist, requiring prolonged treatment and surgical interventions. These so-called persisters display an arrested-growth phenotype, tolerate high antibiotic concentrations, and are associated with chronic and recurrent infections. To characterize these persisters, we assessed S. aureus recovered directly from a patient suffering from a persistent infection. We show that host-mediated stress, including acidic pH, abscess environment, and antibiotic exposure promoted persister formation in vitro and in vivo. Multiomics analysis identified molecular changes in S. aureus in response to acid stress leading to an overall virulent population. However, further analysis of a persister-enriched population revealed major molecular reprogramming in persisters, including down-regulation of virulence and cell division and up-regulation of ribosomal proteins, nucleotide-, and amino acid-metabolic pathways, suggesting their requirement to fuel and maintain the persister phenotype and highlighting that persisters are not completely metabolically inactive. Additionally, decreased aconitase activity and ATP levels and accumulation of insoluble proteins involved in transcription, translation, and energy production correlated with persistence in S. aureus, underpinning the molecular mechanisms that drive the persister phenotype. Upon regrowth, these persisters regained their virulence potential and metabolically active phenotype, including reduction of insoluble proteins, exhibiting a reversible state, crucial for recurrent infections. We further show that a targeted antipersister combination therapy using retinoid derivatives and antibiotics significantly reduced lag-phase heterogeneity and persisters in a murine infection model. Our results provide molecular insights into persisters and help explain why persistent S. aureus infections are so difficult to treat. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Staphylococcus aureus \| antibiotic persistence \| persisters \| antimicrobial therapy \| persistent infection
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180618
作者单位	Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, 8091, Switzerland; Focal AreaInfection Biology, Biozentrum, University of Basel, Basel, 4056, Switzerland; Institute of Biogeochemistry and Pollutant Dynamics, ETH Zurich, Zurich, 8092, Switzerland; Department of Environmental Microbiology, Swiss Federal Institute of Aquatic Science and Technology, Dubendorf, 8600, Switzerland; Department of Pathology and Molecular Pathology, University Hospital Zurich, University of Zurich, Zurich, 8091, Switzerland; Institute of IntensiveCare Medicine, University Hospital Zurich, University of Zurich, Zurich, 8091, Switzerland
推荐引用方式 GB/T 7714	Huemer M.,Shambat S.M.,Bergada-Pijuan J.,et al. Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success[J],2021,118(7).
APA	Huemer M..,Shambat S.M..,Bergada-Pijuan J..,Söderholm S..,Boumasmoud M..,...&Zinkernagel A.S..(2021).Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success.Proceedings of the National Academy of Sciences of the United States of America,118(7).
MLA	Huemer M.,et al."Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success".Proceedings of the National Academy of Sciences of the United States of America 118.7(2021).