biostudies-literatureWinstel VDeutsche ForschungsgemeinschaftNCI NIH HHSNational Institutes of HealthUniversity of California, Los AngelesNIH HHSRP91157https://www.ebi.ac.uk/biostudies/studies/S-EPMC10957174biostudies-literatureUnknown12Host-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 (<i>R</i>)-DI-87, a clinical-stage anticancer drug and potent inhibitor of mammalian deoxycytidine kinase (dCK), mitigates <i>Staphylococcus aureus</i> abscess formation in organ tissues upon invasive bloodstream infection. Mechanistically, (<i>R</i>)-DI-87 shields phagocytes from staphylococcal death-effector deoxyribonucleosides that target dCK and the mammalian purine salvage pathway-apoptosis axis. In this manner, (<i>R</i>)-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.eLifeTargeting host deoxycytidine kinase mitigates <i>Staphylococcus aureus</i> abscess formation.PMC10957174T32CA009120WI4582/2-11R01CA260678-01T32 CA009120R01 CA2606781R01CA25052901A1Winstel VLe TMAbt ERRadu CGfalseTargeting host deoxycytidine kinase mitigates <i>Staphylococcus aureus</i> abscess formation.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 (<i>R</i>)-DI-87, a clinical-stage anticancer drug and potent inhibitor of mammalian deoxycytidine kinase (dCK), mitigates <i>Staphylococcus aureus</i> abscess formation in organ tissues upon invasive bloodstream infection. Mechanistically, (<i>R</i>)-DI-87 shields phagocytes from staphylococcal death-effector deoxyribonucleosides that target dCK and the mammalian purine salvage pathway-apoptosis axis. In this manner, (<i>R</i>)-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.2024-01-01T00:00:00Z2024 Mar2025-04-04T20:07:10.209Z2025-04-04T20:07:10.209ZS-EPMC109571743851272310.7554/eLife.91157