Python Cathelicidin CATHPb1 Protects against Multidrug-Resistant Staphylococcal Infections by Antimicrobial-Immunomodulatory Duality,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Python Cathelicidin CATHPb1 Protects against Multidrug-Resistant Staphylococcal Infections by Antimicrobial-Immunomodulatory Duality
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-21 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00036
Shasha Cai ₁ , Xue Qiao ₁ , Lan Feng ₁ , Nannan Shi ₁ , Hui Wang ₁ , Huaixin Yang ₁ , Zhilai Guo ₂ , Mengke Wang ₁ , Yan Chen ₂ , Yipeng Wang ₂ , Haining Yu ₁

Affiliation

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.

中文翻译：

Python Cathelicidin CATHPb1通过抗微生物-免疫调节双重性保护免受多药耐药的葡萄球菌感染

多重耐药性金黄色葡萄球菌，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，甚至导致败血症和死亡。在这里，我们从Python bivittatu中鉴定了六个新颖的cathelicidins（CATHPb1-6）和CATHPb1表现出最好的体外药理和毒理学特征。我们进一步表明，CATHPb1在小鼠MRSA / VRSA感染模型中表现出明显的保护作用，给予感染前24小时或感染后4小时。该保护通过不同的给药途径都有效，但是由于体内单核细胞/巨噬细胞或嗜中性白细胞的消耗而被阻断。CATHPb1可以快速，大量地调节巨噬细胞/单核细胞和嗜中性粒细胞向感染部位的运输，并增强其杀菌功能。同时，CATHPb1通过促进嗜中性白细胞胞外陷阱（NETs）的形成并防止其降解而显着增强了嗜中性白细胞介导的细菌的杀灭。通过MAPK和NF-κB途径起作用，CATHPb1选择性增强趋化因子的水平，同时减少促炎细胞因子的产生，而不会产生不良毒性。大大提高的血清半衰期和稳定性赋予CATHPb1极好的前景，使其成为对抗多药耐药葡萄球菌感染的新型治疗剂。

更新日期：2018-02-21

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11