Python Cathelicidin CATHPb1 Protects against Multidrug-Resistant Staphylococcal Infections by Antimicrobial-Immunomodulatory Duality

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.