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Nature. 2015 Nov 19;527(7578):323-8. doi: 10.1038/nature16057. Epub 2015 Nov 4.

Novel antibody-antibiotic conjugate eliminates intracellular S. aureus.

Author information

1
Infectious Diseases Department, Genentech Inc., South San Francisco, California 94080, USA.
2
Medicinal Chemistry Department, Genentech Inc., South San Francisco, California 94080, USA.
3
Translational Immunology Department, Genentech Inc., South San Francisco, California 94080, USA.
4
Protein Chemistry Department, Genentech Inc., South San Francisco, California 94080, USA.
5
Biochemical and Cellular Pharmacology Department, Genentech Inc., South San Francisco, California 94080, USA.
6
Structural Biology Department, Genentech Inc., South San Francisco, California 94080, USA.
7
Pathology Department, Genentech Inc., South San Francisco, California 94080, USA.
8
Drug metabolism and Pharmacokinetics Department, Genentech Inc., South San Francisco, California 94080, USA.
9
Symphogen A/S, Pederstrupvej 93, DK-2750 Ballerup, Denmark.

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.

PMID:
26536114
DOI:
10.1038/nature16057
[Indexed for MEDLINE]

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