Molecular reprogramming and phenotype switching in; Staphylococcus aureus; lead to high antibiotic persistence and affect therapy success

Huemer, Markus and Mairpady Shambat, Srikanth and Bergada-Pijuan, Judith and Söderholm, Sandra and Boumasmoud, Mathilde and Vulin, Clément and Gómez-Mejia, Alejandro and Antelo Varela, Minia and Tripathi, Vishwachi and Götschi, Sandra and Marques Maggio, Ewerton and Hasse, Barbara and Brugger, Silvio D. and Bumann, Dirk and Schuepbach, Reto A. and Zinkernagel, Annelies 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). e2014920118.

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Official URL: https://edoc.unibas.ch/87043/

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Infection Biology > Molecular Microbiology (Bumann)
UniBasel Contributors:Bumann, Dirk
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:National Academy of Sciences
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:08 Mar 2022 10:44
Deposited On:08 Mar 2022 10:44

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