Python Cathelicidin CATHPb1 Protects against Multidrug-Resistant Staphylococcal Infections by Antimicrobial-Immunomodulatory Duality
Python Cathelicidin CATHPb1 Protects against Multidrug-Resistant Staphylococcal Infections by Antimicrobial-Immunomodulatory Duality
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Python Cathelicidin CATHPb1 通过抗菌-免疫调节二重性预防多重耐药葡萄球菌感染
DOI：
10.1021/acs.jmedchem.8b00036
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发表时间：
2018-03-08
影响因子：
7.3
通讯作者：
Yu, Haining
中科院分区：
文献类型：
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作者：
Cai, Shasha;Qiao, Xue;Yu, Haining
多重耐药金黄色葡萄球菌，包括MRSA（耐甲氧西林）和VRSA（耐万古霉素），会导致严重的医疗保健相关感染，甚至败血症和死亡。在这里，我们确定了六个新的cathelicidins（CATHPb 1 -6）从蟒蛇bivittatu，和CATHPb 1显示出最好的体外药理学和毒理学资料。我们进一步表明，CATHPb 1在小鼠MRSA/VRSA感染模型中表现出明显的保护作用，无论是在感染前24小时还是感染后4小时。通过不同的给药途径，保护作用都是有效的，但被体内单核细胞/巨噬细胞或中性粒细胞的耗竭所阻断。CATHPb 1可以快速和大量地调节巨噬细胞/单核细胞和中性粒细胞运输到感染部位，并增强其杀菌功能。同时，CATHPb 1通过促进中性粒细胞胞外陷阱（NETs）的形成和阻止其降解，显着增强嗜中性粒细胞介导的细菌杀伤。通过MAPK和NF-κ B途径，CATHPb 1选择性地提高趋化因子的水平，同时减少促炎细胞因子的产生，而没有不良毒性。CATHPb 1的血清半衰期和稳定性大大改善，使其成为一种新型的抗多重耐药葡萄球菌感染的治疗药物具有良好的前景。
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-kappa B 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.