RESUMO
Staphylococcus aureus can cause a broad range of potentially fatal inflammatory complications (e.g., sepsis and endocarditis). Its emerging antibiotic resistance and formidable immune evasion arsenal have emphasized the need for more effective antimicrobial approaches. Complement is an innate immune sensor that rapidly responds to bacterial infection eliciting C3-mediated opsonophagocytic and immunomodulatory responses. Extracellular fibrinogen-binding protein (Efb) is a key immune evasion protein of S. aureus that intercepts complement at the level of C3. To date, Efb has not been explored as a target for mAb-based antimicrobial therapeutics. In this study, we have isolated donor-derived anti-Efb IgGs that attenuate S. aureus survival through enhanced neutrophil killing. A phage library screen yielded mini-Abs that selectively inhibit the interaction of Efb with C3 partly by disrupting contacts essential for complex formation. Surface plasmon resonance-based kinetic analysis enabled the selection of mini-Abs with favorable Efb-binding profiles as therapeutic leads. Mini-Ab-mediated blockade of Efb attenuated S. aureus survival in a whole blood model of bacteremia. This neutralizing effect was associated with enhanced neutrophil-mediated killing of S. aureus, increased C5a release, and modulation of IL-6 secretion. Finally, these mini-Abs afforded protection from S. aureus-induced bacteremia in a murine renal abscess model, attenuating bacterial inflammation in kidneys. Overall, these findings are anticipated to pave the way toward novel Ab-based therapeutics for S. aureus-related diseases.
Assuntos
Anticorpos Antibacterianos/farmacologia , Bacteriemia/tratamento farmacológico , Proteínas de Bactérias/antagonistas & inibidores , Anticorpos de Cadeia Única/farmacologia , Staphylococcus aureus/imunologia , Animais , Anticorpos Antibacterianos/imunologia , Bacteriemia/imunologia , Proteínas de Bactérias/imunologia , Complemento C5a/imunologia , Modelos Animais de Doenças , Humanos , Interleucina-6/imunologia , Camundongos , Anticorpos de Cadeia Única/imunologiaRESUMO
The aerial parts of Inula verbascifolia subsp. methanea yielded three new epoxygermacranolides, compounds 1-3, in addition to the previously known 9beta-hydroxyparthenolide. The structures of 1-3 have been elucidated on the basis of their spectral data (MS, CD, 1D and 2D NMR) and by quantum mechanical calculations. The in vitro cytotoxic activity of compounds 1-3 was evaluated against six human solid tumor cell lines.
