Abstract
Staphylococcus aureus is considered to be an extracellular pathogen. However, survival of S. aureus within host cells may provide a reservoir relatively protected from antibiotics, thus enabling long-term colonization of the host and explaining clinical failures and relapses after antibiotic therapy. Here we confirm that intracellular reservoirs of S. aureus in mice comprise a virulent subset of bacteria that can establish infection even in the presence of vancomycin, and we introduce a novel therapeutic that effectively kills intracellular S. aureus. This antibody-antibiotic conjugate consists of an anti-S. aureus antibody conjugated to a highly efficacious antibiotic that is activated only after it is released in the proteolytic environment of the phagolysosome. The antibody-antibiotic conjugate is superior to vancomycin for treatment of bacteraemia and provides direct evidence that intracellular S. aureus represents an important component of invasive infections.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Anti-Bacterial Agents / pharmacology*
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Anti-Bacterial Agents / therapeutic use
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Bacteremia* / drug therapy
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Bacteremia* / microbiology
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Carrier State / drug therapy
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Carrier State / microbiology
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Drug Design
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Female
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Immunoconjugates / chemistry
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Immunoconjugates / pharmacology*
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Immunoconjugates / therapeutic use*
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Intracellular Space / drug effects
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Intracellular Space / microbiology*
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Methicillin-Resistant Staphylococcus aureus / drug effects
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Methicillin-Resistant Staphylococcus aureus / pathogenicity
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Mice
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Microbial Sensitivity Tests
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Phagosomes / drug effects
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Phagosomes / metabolism
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Phagosomes / microbiology
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Staphylococcal Infections / drug therapy
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Staphylococcal Infections / microbiology*
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Staphylococcal Infections / pathology
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Staphylococcus aureus / drug effects*
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Staphylococcus aureus / pathogenicity
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Vancomycin / pharmacology*
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Vancomycin / therapeutic use
Substances
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Anti-Bacterial Agents
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Immunoconjugates
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Vancomycin