PXD022858-1

PXD022858 is an original dataset announced via ProteomeXchange.

Title	Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success
Description	Staphylococcus aureus causes invasive infections and easily acquires antibiotic resistances. 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, abscesses-environment, and antibiotic exposure promoted persister formation in-vitro and in-vivo. Multi-omics 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 downregulation of virulence and cell division, and upregulation 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 anti-persister 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.
HostingRepository	PRIDE
AnnounceDate	2021-02-12
AnnouncementXML	Submission_2021-02-12_00:35:03.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD022858
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Minia Antelo
SpeciesList	scientific name: Staphylococcus aureus; NCBI TaxID: 1280;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2020-12-01 23:35:55	ID requested
⏵ 1	2021-02-12 00:35:03	announced

Dataset with its publication pending

submitter keyword: Staphylococcus aureus, antibiotic persistence, persisters, host-pathogen interaction, antimicrobial therapy, persistent infection

Dirk Bumann
contact affiliation	Infection Biology Biozentrum, University of Basel CH-4056 Basel, Switzerland Phone: +41 61 207 2382 http://www.biozentrum.unibas.ch/bumann
contact email	dirk.bumann@unibas.ch
lab head
Minia Antelo
contact affiliation	Biozentrum University of Basel
contact email	minia.antelovarela@unibas.ch
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD022858
     1. Label: PRIDE project
     2. Name: Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success