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Targeting host deoxycytidine kinase mitigates Staphylococcus aureus abscess formation
by
Abt, Evan R
, Radu, Caius G
, Winstel, Volker
, Le, Thuc M
in
Abscess
/ Abscesses
/ Adenosine
/ Antibiotics
/ Antimicrobial agents
/ Antimicrobial resistance
/ Antineoplastic drugs
/ Apoptosis
/ Bacteria
/ Bacterial infections
/ Cell death
/ Communicable diseases
/ Cytotoxicity
/ Deoxycytidine kinase
/ Drug resistance
/ Drug resistance in microorganisms
/ Gram-positive bacteria
/ Health aspects
/ Infectious diseases
/ Kinases
/ Laboratory animals
/ Macrophages
/ Microbiology and Infectious Disease
/ Mitochondrial DNA
/ Neutrophils
/ Pathogens
/ Phagocytes
/ Physiological aspects
/ Staphylococcus aureus
/ Staphylococcus aureus infections
/ Staphylococcus infections
2024
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Targeting host deoxycytidine kinase mitigates Staphylococcus aureus abscess formation
by
Abt, Evan R
, Radu, Caius G
, Winstel, Volker
, Le, Thuc M
in
Abscess
/ Abscesses
/ Adenosine
/ Antibiotics
/ Antimicrobial agents
/ Antimicrobial resistance
/ Antineoplastic drugs
/ Apoptosis
/ Bacteria
/ Bacterial infections
/ Cell death
/ Communicable diseases
/ Cytotoxicity
/ Deoxycytidine kinase
/ Drug resistance
/ Drug resistance in microorganisms
/ Gram-positive bacteria
/ Health aspects
/ Infectious diseases
/ Kinases
/ Laboratory animals
/ Macrophages
/ Microbiology and Infectious Disease
/ Mitochondrial DNA
/ Neutrophils
/ Pathogens
/ Phagocytes
/ Physiological aspects
/ Staphylococcus aureus
/ Staphylococcus aureus infections
/ Staphylococcus infections
2024
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Targeting host deoxycytidine kinase mitigates Staphylococcus aureus abscess formation
by
Abt, Evan R
, Radu, Caius G
, Winstel, Volker
, Le, Thuc M
in
Abscess
/ Abscesses
/ Adenosine
/ Antibiotics
/ Antimicrobial agents
/ Antimicrobial resistance
/ Antineoplastic drugs
/ Apoptosis
/ Bacteria
/ Bacterial infections
/ Cell death
/ Communicable diseases
/ Cytotoxicity
/ Deoxycytidine kinase
/ Drug resistance
/ Drug resistance in microorganisms
/ Gram-positive bacteria
/ Health aspects
/ Infectious diseases
/ Kinases
/ Laboratory animals
/ Macrophages
/ Microbiology and Infectious Disease
/ Mitochondrial DNA
/ Neutrophils
/ Pathogens
/ Phagocytes
/ Physiological aspects
/ Staphylococcus aureus
/ Staphylococcus aureus infections
/ Staphylococcus infections
2024
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Targeting host deoxycytidine kinase mitigates Staphylococcus aureus abscess formation
Journal Article
Targeting host deoxycytidine kinase mitigates Staphylococcus aureus abscess formation
2024
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Overview
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 anticancer 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.
Publisher
eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
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