1. Targeting host deoxycytidine kinase mitigates Staphylococcus aureus abscess formation.
- Author
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Winstel, Volker, Abt, Evan R., Le, Thuc M., and Radu, Caius G.
- Subjects
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DEOXYCYTIDINE , *STAPHYLOCOCCUS aureus , *ABSCESSES , *PATHOGENIC microorganisms , *DEOXYRIBONUCLEOSIDES , *MICROBIAL growth - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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