Proteomics

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Stress response within the host affects antibiotic persistence and treatment outcome in Staphylococcus aureus infections


ABSTRACT: Staphylococcus aureus can cause severe invasive infections that require prolonged antibiotic treatment. Although S. aureus can easily acquire antibiotic resistance, even fully susceptible bacteria can persist and survive antibiotic therapy, thus complicating treatment. These so-called persisters are phenotypic variants of bacteria characterized by an arrested-growth phenotype that can tolerate high concentrations of chemotherapeutics and are associated with chronic and recurrent infections. Here, we show that S. aureus recovered directly from infection sites, displayed an increased bacterial lag-phase heterogeneity, forming more non-stable small colonies, indicating the presence of dormant bacteria. Infection modelling showed that host-mediated stress, including acidic pH, neutrophil exposure and murine abscesses, as well as antibiotic treatment, promoted formation of persisters both in vitro and in vivo. Proteomics and RNA-sequencing revealed molecular changes in bacteria in response to acidic stress leading to an overall more virulent population. However, after persister-enrichment, S. aureus displayed downregulation of pathways involved in virulence, cell division, and DNA replication, while ribosomal proteins, nucleotide-, and amino acid- metabolic pathways were upregulated, suggesting their requirement to fuel and maintain the persister phenotype. We demonstrate that decreased aconitase activity and ATP-levels as well as accumulation of insoluble proteins correlated with dormancy and growth reactivation cycles. Combination of antibiotics with retinoid derivatives, especially CD1530, significantly reduced both persisters and total bacterial load in a murine infection model. Our study provides an in-depth characterization of S. aureus persisters and shows that treatment failure due to antibiotic persistence could be addressed by using retinoid derivatives in combination with conventional antibiotics.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Staphylococcus aureus  

TISSUE(S): Tissue Not Applicable To Dataset

DISEASE(S): Not Available

SUBMITTER: Thomas Bock  

LAB HEAD: Alexander Schmidt

PROVIDER: PXD018372 | Pride | 2021-09-09

REPOSITORIES: Pride

Dataset's files

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Action DRS
001_ZN02_C18.raw Raw
001_ZN03_C18.raw Raw
001_ZN04_C19.raw Raw
002_ZN02_C18.raw Raw
002_ZN03_C18.raw Raw
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Publications

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

Huemer Markus M   Mairpady Shambat Srikanth S   Bergada-Pijuan Judith J   Söderholm Sandra S   Boumasmoud Mathilde M   Vulin Clément C   Gómez-Mejia Alejandro A   Antelo Varela Minia M   Tripathi Vishwachi V   Götschi Sandra S   Marques Maggio Ewerton E   Hasse Barbara B   Brugger Silvio D SD   Bumann Dirk D   Schuepbach Reto A RA   Zinkernagel Annelies S AS  

Proceedings of the National Academy of Sciences of the United States of America 20210201 7


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  ...[more]

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