Targeting host deoxycytidine kinase mitigates Staphylococcus aureus abscess formation.

Area of Science:

• Infectious Diseases
• Immunology
• Pharmacology

Background:

• Antimicrobial resistance (AMR) necessitates novel therapeutic strategies.
• Host-directed therapy (HDT) targets host factors, avoiding resistance development.
• Staphylococcus aureus bloodstream infections cause significant morbidity and mortality.

Purpose of the Study:

• To investigate the efficacy of (R)-DI-87, a deoxycytidine kinase (dCK) inhibitor, as a host-directed therapy against Staphylococcus aureus infections.
• To elucidate the mechanism by which (R)-DI-87 mitigates S. aureus-induced pathology.

Main Methods:

• Drug repurposing of (R)-DI-87, a clinical-stage anticancer agent.
• In vivo models of invasive Staphylococcus aureus bloodstream infection and abscess formation.
• Assessment of immune cell function, pathogen burden, and disease severity.

Main Results:

• (R)-DI-87 significantly reduced Staphylococcus aureus abscess formation.
• The drug protected phagocytes from pathogen-induced death-effector deoxyribonucleosides.
• HDT with (R)-DI-87 enhanced macrophage infiltration and pathogen control.
• Ameliorated immunopathology and reduced overall disease severity were observed.

Conclusions:

• Pharmaceutical blockade of deoxycytidine kinase (dCK) is a viable host-directed therapy against Staphylococcus aureus.
• (R)-DI-87 demonstrates potential as an anti-infective agent, particularly for severe infections in hospitalized patients.
• This strategy offers a resistance-proof therapeutic avenue for combating fatal infectious diseases.