1. Targeting host deoxycytidine kinase mitigates Staphylococcus aureus abscess formation
- Author
-
Winstel, Volker, Abt, Evan R, Le, Thuc M, and Radu, Caius G
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Microbiology ,Clinical Sciences ,Medical Microbiology ,Oncology and Carcinogenesis ,Infectious Diseases ,Biotechnology ,Emerging Infectious Diseases ,5.1 Pharmaceuticals ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Development of treatments and therapeutic interventions ,Aetiology ,Infection ,Good Health and Well Being - 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 anti-cancer 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.
- Published
- 2023