Novel antibody–antibiotic conjugate eliminates intracellular S. aureus

Sophie M. Lehar, Thomas Pillow, Min Xu, Leanna Staben, Kimberly K. Kajihara, Richard Vandlen, Laura DePalatis, Helga Raab, Wouter L. Hazenbos, J. Hiroshi Morisaki, Janice Kim, Summer Park, Martine Darwish, Byoung-Chul Lee, Hilda Hernandez, Kelly M. Loyet, Patrick Lupardus, Rina Fong, Donghong Yan, Cecile Chalouni, Elizabeth Luis, Yana Khalfin, Emile Plise, Jonathan Cheong, Joseph P. Lyssikatos, Magnus Strandh, Klaus Koefoed, Peter S. Andersen, John A. Flygare, Man Wah Tan, Eric J. Brown & Sanjeev Mariathasan.

Nature. 2015 Nov 19;527(7578):323-8.

Speaker: Shiau-Ting Yang (楊曉婷)                             Time: 13:00~14:00, May. 11, 2016

Commentator: Dr. Ching-Chuan Liu (劉清泉教授)  Place: Room 601

Abstract:

Staphylococcus aureus (S. aureus) is a gram-positive coccal bacterium that causes important human health problems in both hospital and community settings. In addition, S. aureus is a pathogen that commonly colonizes the respiratory tract and skin of healthy individuals. If the bacteria invade into the bloodstream, serious infections such as osteomyelitis, endocarditis, necrotizing pneumonia and sepsis may occur. Over the past several decades, S. aureus infection has become increasingly hard to cure because of the rapid evolution and spread of drug resistant strains. S. aureus is regarded as an extracellular bacterium, but previous researches have demonstrated that S. aureus is able to invade and survive inside mammalian cells, including the epithelial cells, osteoclasts and phagocytic cells ^[1]. Survival of S. aureus within host cells may provide a protective reservoir to defend against antibiotics, this is one reason that S. aureus can colonize in the human body for a long time and cause chronic or recurrent infections after antibiotic therapy. Eliminating intracellular S. aureus is a key to clinical success, however there has been no means to prove this hypothesis directly until now. In this article the authors confirmed that intracellular S. aureus possess invasive, survival and disseminative abilities to establish infection even under vancomycin treatment. The authors next designed a novel therapeutic way that effectively kills intracellular S. aureus. This antibody–antibiotic conjugate (AAC) is consists of an anti-S. aureus antibody linked to a rifamycin derivative that is fully activated only after its linker is cleaved by the phagosome protease. The AACs can eradicate intracellular S. aureus infection and are superior to vancomycin treatment. Furthermore, the authors provide direct evidence that the intracellular S. aureus truly plays an important role in invasive infections.

References:

1.     Garzoni C, Kelley WL. (2009) Staphylococcus aureus: new evidence for intracellular persistence. Trends in microbiology. 17, 59-65.