The Stringent Response Contributes to Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection Through the Purine Biosynthetic Pathway.
Animals
Anti-Bacterial Agents
/ therapeutic use
Bacteremia
/ metabolism
Biosynthetic Pathways
Disease Models, Animal
Endocarditis
/ metabolism
Humans
Methicillin
/ pharmacology
Methicillin-Resistant Staphylococcus aureus
/ pathogenicity
Purines
/ biosynthesis
Rabbits
Staphylococcal Infections
/ metabolism
MRSA
(p)ppGpp
endovascular infection
persistence
purine biosynthesis
stringent response
Journal
The Journal of infectious diseases
ISSN: 1537-6613
Titre abrégé: J Infect Dis
Pays: United States
ID NLM: 0413675
Informations de publication
Date de publication:
01 09 2020
01 09 2020
Historique:
received:
16
01
2020
accepted:
21
04
2020
pubmed:
26
4
2020
medline:
5
3
2021
entrez:
26
4
2020
Statut:
ppublish
Résumé
Persistent methicillin-resistant Staphylococcus aureus (MRSA) endovascular infections represent a significant clinical-therapeutic challenge. Of particular concern is antibiotic treatment failure in infections caused by MRSA that are "susceptible" to antibiotic in vitro. In the current study, we investigate specific purine biosynthetic pathways and stringent response mechanism(s) related to this life-threatening syndrome using genetic matched persistent and resolving MRSA clinical bacteremia isolates (PB and RB, respectively), and isogenic MRSA strain sets. We demonstrate that PB isolates (vs RB isolates) have significantly higher (p)ppGpp production, phenol-soluble-modulin expression, polymorphonuclear leukocyte lysis and survival, fibronectin/endothelial cell (EC) adherence, and EC damage. Importantly, an isogenic strain set, including JE2 parental, relP-mutant and relP-complemented strains, translated the above findings into significant outcome differences in an experimental endocarditis model. These observations indicate a significant regulation of purine biosynthesis on stringent response, and suggest the existence of a previously unknown adaptive genetic mechanism in persistent MRSA infection.
Identifiants
pubmed: 32333768
pii: 5825247
doi: 10.1093/infdis/jiaa202
pmc: PMC7459137
doi:
Substances chimiques
Anti-Bacterial Agents
0
Purines
0
Methicillin
Q91FH1328A
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1188-1198Subventions
Organisme : NIAID NIH HHS
ID : R01 AI139244
Pays : United States
Organisme : NIAID NIH HHS
ID : R33 AI111661
Pays : United States
Organisme : NIAID NIH HHS
ID : U01 AI124319
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI130056
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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