Novel antibody–antibiotic conjugate eliminates intracellular S. aureus

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.



a, Model of AAC (not drawn to scale). b, Mechanism of AAC action. c, Binding of Alexa-488 anti-β-GlcNAC WTA monoclonal antibody (mAb) or anti-α-GlcNAC WTA monoclonal antibody, or isotype control antibody, anti-cytomegalovirus glycoprotein-D (gD) to USA300 isolated from infected kidneys (n = 3). MFI, mean fluorescence intensity. d, Binding of anti-GlcNAC WTA antibodies (red) or isotype control (grey) to protein-A-deficient USA300 lacking tarM or tarS (n = 3). WT, wild type. e, Crystal structure of anti-β-GlcNAc WTA Fab bound to a synthetic minimal β-WTA unit. Antibody light chain (pink) and heavy chain (blue) are shown. f, MIC determination for rifampicin and rifalogue on USA300 (n = 5). g, Survival of stationary phase USA300 incubated with 1 × 10−6 M rifampicin or rifalogue (n = 4). h, USA300 bacteria were incubated without antibiotic (black) or with 3 μg ml−1 ciprofloxacin (Cipro; green, red and grey). 1 μg ml−1 of rifalogue (red) or rifampicin (grey) was added as indicated (n = 3). i, Intact AAC does not kill planktonic bacteria but does after pre-treatment with cathepsin-B (n = 3). g–i, Error bars show s.d. for triplicate samples (n = biological repeats).

Enlace al trabajo