PXD018332

PXD018332 is an original dataset announced via ProteomeXchange.

Title	Stress adaptation within the host effects antibiotic tolerance and treatment outcome in Staphylococcus aureus infections
Description	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 stress-response reactions in bacteria leading to an overall more virulent population. However, after persister-enrichment, S. aureus displayed down-regulation of pathways involved in virulence, cell division, and DNA replication, while ribosomal proteins, nucleotide-, and amino acid- metabolic pathways were up-regulated, 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.
HostingRepository	PRIDE
AnnounceDate	2021-02-12
AnnouncementXML	Submission_2021-02-12_00:54:32.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD018332
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Markus Huemer
SpeciesList	scientific name: Staphylococcus aureus; NCBI TaxID: 1280;
ModificationList	Oxidation; monohydroxylated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2020-04-01 23:05:00	ID requested
⏵ 1	2021-02-12 00:54:32	announced

Dataset with its publication pending

submitter keyword: Staphylococcus aureus, antibiotic persistence, stress response

Annelies S. Zinkernagel
contact affiliation	Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Switzerland
contact email	annelies.zinkernagel@usz.ch
lab head
Markus Huemer
contact affiliation	University of Zurich
contact email	markus.huemer@usz.ch
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD018332
     1. Label: PRIDE project
     2. Name: Stress adaptation within the host effects antibiotic tolerance and treatment outcome in Staphylococcus aureus infections