2023/10/11 by Volker Winstel, Evan R. Abt, Caius G. Radu · 1 voice
Medicine · Biochemistry, Genetics and Molecular Biology · #Antimicrobial Resistance in Staphylococcus #Bacterial biofilms and quorum sensing #Microbial Metabolism and Applications
paper · pdf · doi:10.7554/elife.91157.1
openalex publication_date 2023/10/11 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/31
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), attenuates the virulence of antibiotic-resistant Staphylococcus aureus in a mouse model of 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.