Doctor of Philosophy (PhD)
Joseph A. Vetro
Staphylococcus aureus is the most common cause of bacterial skin and soft tissue infections (SSTIs) and the leading cause of hospital-associated infections in the United States. The abundance of S. aureus infections is due, in part, to its virulence factors that suppress host immune system and the development of antibiotic resistance strains such as methicillin-resistant S. aureus (MRSA). In contrast to antibiotics, Host-Directed Therapeutics (HDTs), avoid the pitfalls of antibiotics by targeting the host for immune system rather than targeting the pathogen. This mechanism of action avoids selective evolutionary pressure, which leads to antibiotic resistance and helps the host immune system overcome bacterial virulence factor-based immunosuppression. Complement Peptide-Derived Immunostimulant-02 (CPDI-02) is a novel, second-generation host-derived decapeptide agonist of C5a Receptor 1 (C5aR1) based on the C-terminal pharmacophore of human complement C5a. Unlike its parent compound, CPDI-02 can selectively stimulate C5aR1 on mononuclear phagocytes with 103 -fold potency over polynuclear phagocytes. This activity allows CPDI-02 to serve as an HDT, stimulating the host's innate immune response to fight infection without neutrophil and inflammation-mediated toxicity. CPDI-02 reduces the bacterial burden within bacterial-induced abscess wounds on outbred CD-1 mice when intramuscularly administered six hours post-challenge in murine models. It also reduces the time to resolve the infection-induced iv abscess in a murine dermal MRSA infection model. CPDI-02 induces this therapeutic effect by interacting with host mononuclear phagocytes and promoting infiltration of these cells into the abscessed tissue. Intramuscularly administration of CPDI-02 is well tolerated by healthy male and female CD-1 mice to between 130 and 170 mg/kg. In addition to its therapeutic qualities in murine models, CPDI-02 is also shown to help improve wound healing in porcine wound models by reducing bacterial-induced inhibition to wound closure, thus helping improve infected wound healing. The in vivo activity suggests that CPDI-02 can move the timeline of mononuclear phagocyte involvement in response to infection earlier than in untreated infections. The earlier involvement of mononuclear phagocytes in infection, in turn, reduces damage to host tissue which comes from the invading bacteria and the host's inflammatory response.
Stewart, Jason P., "Intramuscular Administration of the Host-Derived Immunostimulant CPDI-02 Increases Protection of Outbred Mice and Piglets Against Dermal MRSA Infection in a Curative Setting and is Well Tolerated After Repeated Administration" (2023). Theses & Dissertations. 726.
Available for download on Wednesday, April 09, 2025