Python Cathelicidin CATHPb1 Protects against Multidrug-Resistant Staphylococcal Infections by Antimicrobial-Immunomodulatory Duality
Shasha Cai1, Xue Qiao1, Lan Feng1
1School of Life Science and Biotechnology , Dalian University of Technology , Dalian , Liaoning 116024 , China.
Abstract:
Multidrug-resistant Staphylococcus aureus, including MRSA (methicillin-resistant) and VRSA (vancomycin-resistant), causes serious healthcare-associated infections, even sepsis and death. Here, we identified six novel cathelicidins (CATHPb1-6) from Python bivittatu, and CATHPb1 displayed the best in vitro pharmacological and toxicological profile. We further show that CATHPb1 exhibited evident protection in mice MRSA/VRSA infection models, given either 24 h before or 4 h after infection. The protection was all effective through different administration routes, but was blocked by in vivo depletion of monocyte/macrophages or neutrophils. CATHPb1 can rapidly and massively modulate macrophages/monocytes and neutrophils trafficking to the infection site, and potentiate their bactericidal functions. Meanwhile, CATHPb1 remarkably augmented neutrophil-mediated bacteria killing by facilitating neutrophil extracellular traps (NETs) formation and preventing its degradation. Acting through MAPKs and NF-κB pathways, CATHPb1 selectively enhanced the levels of chemokines while reducing the production of pro-inflammatory cytokines without undesirable toxicities. The much improved serum half-life and stabilities confer CATHPb1 an excellent prospect to become a novel therapeutic agent against multidrug-resistant staphylococcal infections.
Insights
Researchers discovered novel cathelicidins from Python bivittatu, with CATHPb1 showing potent protection against multidrug-resistant Staphylococcus aureus infections in mice by enhancing immune cell activity.
Area of Science:
- Antimicrobial Peptides
- Immunology
- Infectious Diseases
Background:
- Multidrug-resistant Staphylococcus aureus, including methicillin-resistant (MRSA) and vancomycin-resistant (VRSA) strains, pose significant threats, causing severe healthcare-associated infections.
- Novel therapeutic strategies are urgently needed to combat the rising challenge of antibiotic resistance.
Purpose of the Study:
- To identify and characterize novel cathelicidins with antimicrobial properties.
- To evaluate the therapeutic potential of a lead cathelicidin candidate against multidrug-resistant Staphylococcus aureus infections.
Main Methods:
- Identification and in vitro characterization of six novel cathelicidins (CATHPb1-6) from Python bivittatu.
- In vivo efficacy studies in mouse models of MRSA/VRSA infection, assessing protection with different administration timings and routes.
- Investigation of the underlying mechanisms, including immune cell modulation, chemokine and cytokine production, and signaling pathways (MAPKs, NF-κB).
Main Results:
- CATHPb1 demonstrated the best in vitro pharmacological and toxicological profile among the identified cathelicidins.
- CATHPb1 provided significant protection against MRSA/VRSA infections in mice, regardless of administration timing (24h before or 4h after infection) or route.
- Protection was dependent on monocytes/macrophages and neutrophils, as CATHPb1 enhanced their trafficking and bactericidal functions, including neutrophil extracellular trap (NET) formation.
- CATHPb1 modulated immune responses by enhancing chemokines and reducing pro-inflammatory cytokines via MAPK and NF-κB pathways, without significant toxicity.
Conclusions:
- CATHPb1 is a promising novel therapeutic agent against multidrug-resistant staphylococcal infections due to its efficacy, immune-modulating properties, and favorable pharmacokinetic profile.
- Further development of CATHPb1 could offer a new treatment option for challenging bacterial infections.
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