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Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Feb 16; Vol. 118 (7). - Publication Year :
- 2021
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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.<br />Competing Interests: The authors declare no competing interest.
- Subjects :
- Aconitate Hydratase metabolism
Adenosine Triphosphate metabolism
Animals
Anti-Bacterial Agents pharmacology
Anti-Bacterial Agents therapeutic use
Bacterial Proteins genetics
Bacterial Proteins metabolism
Cells, Cultured
Humans
Mice
Mice, Inbred C57BL
Ribosomal Proteins genetics
Ribosomal Proteins metabolism
Staphylococcal Infections drug therapy
Staphylococcus aureus genetics
Staphylococcus aureus metabolism
Staphylococcus aureus pathogenicity
Drug Resistance, Bacterial
Metabolome
Phenotype
Staphylococcal Infections microbiology
Staphylococcus aureus drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 118
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 33574060
- Full Text :
- https://doi.org/10.1073/pnas.2014920118