Targeting host deoxycytidine kinase mitigates Staphylococcus aureus abscess formation.
Volker WinstelEvan R AbtThuc M LeCaius G RaduPublished in: eLife (2024)
Host-directed therapy (HDT) is an emerging approach to overcome antimicrobial resistance in pathogenic microorganisms. Specifically, HDT targets host-encoded factors required for pathogen replication and survival without interfering with microbial growth or metabolism, thereby eliminating the risk of resistance development. By applying HDT and a drug repurposing approach, we demonstrate that ( R )-DI-87, a clinical-stage anticancer drug and potent inhibitor of mammalian deoxycytidine kinase (dCK), mitigates Staphylococcus aureus abscess formation in organ tissues upon invasive bloodstream infection. Mechanistically, ( R )-DI-87 shields phagocytes from staphylococcal death-effector deoxyribonucleosides that target dCK and the mammalian purine salvage pathway-apoptosis axis. In this manner, ( R )-DI-87-mediated protection of immune cells amplifies macrophage infiltration into deep-seated abscesses, a phenomenon coupled with enhanced pathogen control, ameliorated immunopathology, and reduced disease severity. Thus, pharmaceutical blockade of dCK represents an advanced anti-infective intervention strategy against which staphylococci cannot develop resistance and may help to fight fatal infectious diseases in hospitalized patients.
Keyphrases
- staphylococcus aureus
- antimicrobial resistance
- biofilm formation
- infectious diseases
- candida albicans
- randomized controlled trial
- methicillin resistant staphylococcus aureus
- pseudomonas aeruginosa
- tyrosine kinase
- gene expression
- protein kinase
- microbial community
- endoplasmic reticulum stress
- stem cells
- cell death
- escherichia coli
- mesenchymal stem cells
- cell cycle arrest
- anti inflammatory
- radiation therapy
- immune response
- emergency department
- free survival
- signaling pathway
- klebsiella pneumoniae
- gram negative
- smoking cessation
- type iii
- pi k akt