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dc.contributor.author
Huemer, Markus
dc.contributor.author
Mairpady Shambat, Srikanth
dc.contributor.author
Bergada-Pijuan, Judith
dc.contributor.author
Söderholm, Sandra
dc.contributor.author
Boumasmoud, Mathilde
dc.contributor.author
Vulin, Clément
dc.contributor.author
Gómez-Mejia, Alejandro
dc.contributor.author
Antelo Varela, Minia
dc.contributor.author
Tripathi, Vishwachi
dc.contributor.author
Maggio, Ewerton M.
dc.contributor.author
Hasse, Barbara
dc.contributor.author
Brugger, Silvio D.
dc.contributor.author
Bumann, Dirk
dc.contributor.author
Schuepbach, Reto A.
dc.contributor.author
Zinkernagel, Annelies S.
dc.date.accessioned
2021-03-01T13:47:01Z
dc.date.available
2021-03-01T05:03:25Z
dc.date.available
2021-03-01T13:47:01Z
dc.date.issued
2021-02-16
dc.identifier.issn
0027-8424
dc.identifier.issn
1091-6490
dc.identifier.other
10.1073/pnas.2014920118
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/472080
dc.description.abstract
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.
en_US
dc.language.iso
en
en_US
dc.publisher
National Academy of Sciences
en_US
dc.subject
Staphylococcus aureus
en_US
dc.subject
antibiotic persistence
en_US
dc.subject
persisters
en_US
dc.subject
antimicrobial therapy
en_US
dc.subject
persistent infection
en_US
dc.title
Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success
en_US
dc.type
Journal Article
dc.date.published
2021-02-11
ethz.journal.title
Proceedings of the National Academy of Sciences of the United States of America
ethz.journal.volume
118
en_US
ethz.journal.issue
7
en_US
ethz.journal.abbreviated
Proc Natl Acad Sci U S A
ethz.pages.start
e2014920118
en_US
ethz.size
12 p.
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Washington, DC
en_US
ethz.publication.status
published
en_US
ethz.date.deposited
2021-03-01T05:03:39Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Metadata only
en_US
ethz.rosetta.installDate
2021-03-01T13:47:11Z
ethz.rosetta.lastUpdated
2022-03-29T05:31:11Z
ethz.rosetta.versionExported
true
ethz.COinS
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