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Edited by Staffan Normark, Karolinska Institute, Stockholm, Sweden, and approved January 8, 2021 (received for review July 17, 2020)
Significance
Persisters represent a bacterial subpopulation that survive high antibiotic concentrations without being resistant. Their role in clinics in persistent infections and their molecular and functional landscape is not fully established. Staphylococcus aureus is a pathobiont that causes severe invasive infections often difficult to treat. Here, we assessed S. aureus recovered directly from persistent infections and show that host-mediated stress and antibiotic exposure promoted persister formation. Using a multiomics approach and enrichment of persisters, we were able to draw a molecular atlas of persisters, to correlate accumulation of insoluble proteins and ATP depletion with dormancy and persistence. Our results give insights into the molecular profile of bacterial persisters and provide a guide for therapy optimization for persistent S. aureus infections.
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.
Footnotes
↵1M.H. and S.M.S. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: annelies.zinkernagel{at}usz.ch.
Author contributions: M.H., S.M.S., R.A.S., and A.S.Z. designed research; M.H., S.M.S., J.B.-P., S.S., C.V., A.G.-M., M.A.V., V.T., and S.G. performed research; E.M.M., B.H., D.B., R.A.S., and A.S.Z. contributed new reagents/analytic tools; M.H., S.M.S., J.B.-P., S.S., M.B., C.V., S.D.B., D.B., and R.A.S. analyzed data; E.M.M. performed histological stainings and analysis; and M.H., S.M.S., and A.S.Z. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2014920118/-/DCSupplemental.
Data Availability.
Raw data have been deposited in European Nucleotide Archive (ENA): PRJEB37630 (27); Gene Expression Omnibus (GEO): GSE148024 (34); and PRIDE: PXD018372 (33), PXD018332 (37), and PXD022858 (35) and are publicly available. All other study data are included in the article and supporting information.
Published under the PNAS license.
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Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success
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