Targeting host deoxycytidine kinase mitigates Staphylococcus aureus abscess formation

Area of Science:

• Microbiology
• Immunology
• Pharmacology

Background:

• Antimicrobial resistance poses a significant threat to public health.
• Host-directed therapy (HDT) offers a promising strategy to combat resistant pathogens by targeting host factors.
• Staphylococcus aureus bloodstream infections can lead to severe abscess formation and systemic disease.

Approach:

• Utilized a drug repurposing strategy combined with HDT.
• Investigated the efficacy of (R)-DI-87, a clinical-stage anti-cancer drug and inhibitor of mammalian deoxycytidine kinase (dCK), against S. aureus infections.
• Examined the mechanistic basis of (R)-DI-87's protective effects in host cells.

Key Points:

• (R)-DI-87 mitigates Staphylococcus aureus abscess formation in invasive bloodstream infections.
• The drug protects phagocytes from pathogen-induced damage by inhibiting host dCK and the purine salvage pathway-apoptosis axis.
• This protection enhances macrophage infiltration into abscesses, leading to improved pathogen control and reduced disease severity.

Conclusions:

• Pharmaceutical blockade of dCK represents a novel anti-infective strategy against which bacteria cannot develop resistance.
• (R)-DI-87 demonstrates potential as an effective therapeutic agent for fatal infectious diseases, particularly in hospitalized patients.
• HDT targeting dCK offers a promising avenue for developing next-generation anti-infectives to combat resistant bacteria.