Protein-inspired antibiotics active against vancomycin- and daptomycin-resistant bacteria.
Protein-inspired antibiotics active against vancomycin- and daptomycin-resistant bacteria.
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DOI：
10.1038/s41467-017-02123-w
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发表时间：
2018-01-02
影响因子：
16.6
通讯作者：
Cooper MA
中科院分区：
文献类型：
--
作者：
Blaskovich MAT;Hansford KA;Gong Y;Butler MS;Muldoon C;Huang JX;Ramu S;Silva AB;Cheng M;Kavanagh AM;Ziora Z;Premraj R;Lindahl F;Bradford TA;Lee JC;Karoli T;Pelingon R;Edwards DJ;Amado M;Elliott AG;Phetsang W;Daud NH;Deecke JE;Sidjabat HE;Ramaologa S;Zuegg J;Betley JR;Beevers APG;Smith RAG;Roberts JA;Paterson DL;Cooper MA
“后抗生素”时代的到来对公共卫生构成了威胁，需要新的方法来发现抗生素。药物开发通常避免利用膜结合特性，这与自然界通过调节膜相关蛋白和膜脂质组成来控制生物途径相反。在这里，我们描述了复活的糖肽抗生素万古霉素通过选择性靶向细菌膜。将基于带正电荷的静电效应子序列的肽文库连接至N末端亲脂性膜插入元件，然后缀合至万古霉素。这些修饰的脂糖肽，即“vancapticins”，具有增强的膜亲和力和对耐甲氧西林金黄色葡萄球菌（MRSA）和其他革兰氏阳性细菌的活性，并保留对糖肽耐药菌株的活性。优化的抗生素在多种细菌感染模型中显示出体内功效。这种膜靶向策略有可能“重振”对寄生菌失去效力的抗生素，或增强其他靶向膜相关受体的静脉内给药药物的活性。抗生素万古霉素通过与膜相关前体结合来抑制细菌细胞壁的合成。在此，Blaskovich等人合成了含有亲脂性肽部分的万古霉素衍生物，其增强了膜亲和力和对糖肽耐药菌株的体内活性。
The public health threat posed by a looming ‘post-antibiotic’ era necessitates new approaches to antibiotic discovery. Drug development has typically avoided exploitation of membrane-binding properties, in contrast to nature’s control of biological pathways via modulation of membrane-associated proteins and membrane lipid composition. Here, we describe the rejuvenation of the glycopeptide antibiotic vancomycin via selective targeting of bacterial membranes. Peptide libraries based on positively charged electrostatic effector sequences are ligated to N-terminal lipophilic membrane-insertive elements and then conjugated to vancomycin. These modified lipoglycopeptides, the ‘vancapticins’, possess enhanced membrane affinity and activity against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria, and retain activity against glycopeptide-resistant strains. Optimised antibiotics show in vivo efficacy in multiple models of bacterial infection. This membrane-targeting strategy has potential to ‘revitalise’ antibiotics that have lost effectiveness against recalcitrant bacteria, or enhance the activity of other intravenous-administered drugs that target membrane-associated receptors. The antibiotic vancomycin inhibits bacterial cell wall synthesis by binding to a membrane-associated precursor. Here, Blaskovich et al. synthesize vancomycin derivatives containing lipophilic peptide moieties that enhance membrane affinity and in vivo activities against glycopeptide-resistant strains.
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影响因子：
9.4
作者：
Hayden, MK;Rezai, K;Weinstein, RA
通讯作者：
Weinstein, RA
影响因子：
2.9
作者：
CHATTOPADHYAY, A;LONDON, E
通讯作者：
LONDON, E
影响因子：
4.9
作者：
Mani, N;Gross, CH;Grossman, TH
通讯作者：
Grossman, TH
DOI：
10.1016/j.bbagen.2005.06.015
发表时间：
2005-10-30
影响因子：
3
作者：
Dufour, S;Deleu, M;Paquot, M
通讯作者：
Paquot, M
影响因子：
5.8
作者：
Di, L;Kerns, EH;Chen, H
通讯作者：
Chen, H