Synthetic antibacterial discovery of symbah-1, a macrocyclic β-hairpin peptide antibiotic.
Synthetic antibacterial discovery of symbah-1, a macrocyclic β-hairpin peptide antibiotic.
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DOI：
10.1016/j.isci.2021.103611
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发表时间：
2022-01-21
期刊：
影响因子：
5.8
通讯作者：
Davies BW
中科院分区：
文献类型：
--
作者：
Randall JR;Davidson G;Fleeman RM;Acosta SA;Riddington IM;Cole TJ;DuPai CD;Davies BW
抗生素耐药性的快速发展和传播需要开发新的抗生素发现策略。在随机肽序列的高通量抗菌筛选中鉴定了合成肽抗生素Symbah-1。Symbah-1通过膜破坏发挥作用，对多种耐药病原体具有广谱杀菌活性。圆二色谱和高分辨质谱分析表明，symbah-1在脂多糖诱导下形成β-发夹结构，并通过分子内二硫键环化。这些数据一起将symbah-1分类为β-发夹抗菌肽类的不常见合成成员。Symbah-1显示低溶血性，但在人血清中失去活性。对symbah-1肽库的表征鉴定了具有增加的血清活性和蛋白酶抗性的两种变体。symbah-1的发现方法和随后的表征表明，可以设计和筛选偏向大环β-发夹结构的大型合成肽文库，以快速扩增和更好地理解这种罕见的肽抗生素类别。合成肽展示屏鉴定大环β-发夹肽抗生素Symbah-1通过破坏细菌膜杀死，但不具有溶血性Symbah-1在人血清中失去活性，可能是由于结构不稳定性结构优化通过降低蛋白酶不稳定性提高其血清活性生物化学;微生物学;结构生物学
The rapid development and spread of antibiotic resistance necessitate the development of novel strategies for antibiotic discovery. Symbah-1, a synthetic peptide antibiotic, was identified in a high-throughput antibacterial screen of random peptide sequences. Symbah-1 functions through membrane disruption and contains broad spectrum bactericidal activity against several drug-resistant pathogens. Circular dichroism and high-resolution mass spectrometry indicate symbah-1 has a β-hairpin structure induced by lipopolysaccharide and is cyclized via an intramolecular disulfide bond. Together these data classify symbah-1 as an uncommon synthetic member of the β-hairpin antimicrobial peptide class. Symbah-1 displays low hemolysis but loses activity in human serum. Characterization of a symbah-1 peptide library identified two variants with increased serum activity and protease resistance. The method of discovery and subsequent characterization of symbah-1 suggests large synthetic peptide libraries bias toward macrocyclic β-hairpin structure could be designed and screened to rapidly expand and better understand this rare peptide antibiotic class. Synthetic peptide display screen identifies a macrocyclic β-hairpin peptide antibiotic Symbah-1 kills through disrupting bacterial membranes, yet is not very hemolytic Symbah-1 loses activity in human serum, likely due to structural instability Structural optimization improves its serum activity by reducing its protease lability Biochemistry; Microbiology; Structural biology
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影响因子：
8
作者：
DuPai, Cory D.;Davies, Bryan W.;Wilke, Claus O.
通讯作者：
Wilke, Claus O.
影响因子：
5.7
作者：
Martin-Loeches, Ignacio;Dale, Glenn E.;Torres, Antoni
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Torres, Antoni
影响因子：
6.1
作者：
CONNOLLY, ML
通讯作者：
CONNOLLY, ML
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
5.8
作者：
Mirdita, Milot;Steinegger, Martin;Soeding, Johannes
通讯作者：
Soeding, Johannes