A pleurocidin analogue with greater conformational flexibility, enhanced antimicrobial potency and in vivo therapeutic efficacy.
A pleurocidin analogue with greater conformational flexibility, enhanced antimicrobial potency and in vivo therapeutic efficacy.
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一种具有更大构象灵活性、增强的抗微生物效力和体内治疗功效的pleurocidin类似物。
DOI：
10.1038/s42003-020-01420-3
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发表时间：
2020-11-27
影响因子：
5.9
通讯作者：
Mason AJ
中科院分区：
文献类型：
--
作者：
Manzo G;Hind CK;Ferguson PM;Amison RT;Hodgson-Casson AC;Ciazynska KA;Weller BJ;Clarke M;Lam C;Man RCH;Shaughnessy BGO;Clifford M;Bui TT;Drake AF;Atkinson RA;Lam JKW;Pitchford SC;Page CP;Phoenix DA;Lorenz CD;Sutton JM;Mason AJ
抗菌肽是一种潜在的替代经典抗生素的药物，但在治疗全身性感染方面尚未取得突破性进展。pleurocidin是一种来自Winter Flounder的AMP，其抗菌效力与其穿过细菌质膜并寻找细胞内靶点的能力有关，同时也引起膜损伤。在这里，我们描述的修改策略，产生pleurocidin类似物，大大改善，广谱，抗菌性能，这是有效的细菌性肺部感染的小鼠模型。增加肽-脂质分子间氢键结合能力增强了与膜易位相关的构象灵活性，但也增强了膜损伤和效力，最显著的是针对革兰氏阳性细菌。这否定了它们在代谢上适应AMP威胁的能力。包含d-氨基酸的类似物在15 mg/kg的静脉内剂量下耐受良好，并且在减少EMRSA-15肺CFU方面与万古霉素类似有效。这突出了全身递送的杀菌AMP的治疗潜力。Manzo等人描述了具有显著改善的抗菌性质、构象灵活性和针对细菌性肺部感染的鼠模型的治疗功效的多种pleurocidin类似物的开发。在体内小鼠EMRSA肺模型中，最有前途的类似物与万古霉素一样有效。
Antimicrobial peptides (AMPs) are a potential alternative to classical antibiotics that are yet to achieve a therapeutic breakthrough for treatment of systemic infections. The antibacterial potency of pleurocidin, an AMP from Winter Flounder, is linked to its ability to cross bacterial plasma membranes and seek intracellular targets while also causing membrane damage. Here we describe modification strategies that generate pleurocidin analogues with substantially improved, broad spectrum, antibacterial properties, which are effective in murine models of bacterial lung infection. Increasing peptide–lipid intermolecular hydrogen bonding capabilities enhances conformational flexibility, associated with membrane translocation, but also membrane damage and potency, most notably against Gram-positive bacteria. This negates their ability to metabolically adapt to the AMP threat. An analogue comprising d-amino acids was well tolerated at an intravenous dose of 15 mg/kg and similarly effective as vancomycin in reducing EMRSA-15 lung CFU. This highlights the therapeutic potential of systemically delivered, bactericidal AMPs. Manzo et al. describe the development of multiple pleurocidin analogues with substantially improved antibacterial properties, conformational flexibility and therapeutic efficacy against murine models of bacterial lung infection. The most promising analogue is as effective as vancomycin in an in vivo mouse EMRSA lung model.
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影响因子：
4.6
作者：
Amos ST;Vermeer LS;Ferguson PM;Kozlowska J;Davy M;Bui TT;Drake AF;Lorenz CD;Mason AJ
通讯作者：
Mason AJ
影响因子：
2.1
作者：
Epand, Richard M.;Epand, Raquel F.
通讯作者：
Epand, Raquel F.
影响因子：
5.8
作者：
Gautier, Romain;Douguet, Dominique;Drin, Guillaume
通讯作者：
Drin, Guillaume
DOI：
10.1165/rcmb.2017-0083oc
发表时间：
2018-03-01
影响因子：
6.4
作者：
Amison, Richard T.;O'Shaughnessy, Blaze G.;Page, Clive P.
通讯作者：
Page, Clive P.
影响因子：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.