Publication Date:
2015-11-05
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lehar, Sophie M -- Pillow, Thomas -- Xu, Min -- Staben, Leanna -- Kajihara, Kimberly K -- Vandlen, Richard -- DePalatis, Laura -- Raab, Helga -- Hazenbos, Wouter L -- Morisaki, J Hiroshi -- Kim, Janice -- Park, Summer -- Darwish, Martine -- Lee, Byoung-Chul -- Hernandez, Hilda -- Loyet, Kelly M -- Lupardus, Patrick -- Fong, Rina -- Yan, Donghong -- Chalouni, Cecile -- Luis, Elizabeth -- Khalfin, Yana -- Plise, Emile -- Cheong, Jonathan -- Lyssikatos, Joseph P -- Strandh, Magnus -- Koefoed, Klaus -- Andersen, Peter S -- Flygare, John A -- Wah Tan, Man -- Brown, Eric J -- Mariathasan, Sanjeev -- England -- Nature. 2015 Nov 19;527(7578):323-8. doi: 10.1038/nature16057. Epub 2015 Nov 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Infectious Diseases Department, Genentech Inc., South San Francisco, California 94080, USA. ; Medicinal Chemistry Department, Genentech Inc., South San Francisco, California 94080, USA. ; Translational Immunology Department, Genentech Inc., South San Francisco, California 94080, USA. ; Protein Chemistry Department, Genentech Inc., South San Francisco, California 94080, USA. ; Biochemical and Cellular Pharmacology Department, Genentech Inc., South San Francisco, California 94080, USA. ; Structural Biology Department, Genentech Inc., South San Francisco, California 94080, USA. ; Pathology Department, Genentech Inc., South San Francisco, California 94080, USA. ; Drug metabolism and Pharmacokinetics Department, Genentech Inc., South San Francisco, California 94080, USA. ; Symphogen A/S, Pederstrupvej 93, DK-2750 Ballerup, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26536114" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Anti-Bacterial Agents/*pharmacology/therapeutic use
;
*Bacteremia/drug therapy/microbiology
;
Carrier State/drug therapy/microbiology
;
Drug Design
;
Female
;
Immunoconjugates/chemistry/*pharmacology/*therapeutic use
;
Intracellular Space/drug effects/*microbiology
;
Methicillin-Resistant Staphylococcus aureus/drug effects/pathogenicity
;
Mice
;
Microbial Sensitivity Tests
;
Phagosomes/drug effects/metabolism/microbiology
;
Staphylococcal Infections/drug therapy/*microbiology/pathology
;
Staphylococcus aureus/*drug effects/pathogenicity
;
Vancomycin/*pharmacology/therapeutic use
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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