Ab initio design of potent anti-MRSA peptides based on database filtering technology.
Ab initio design of potent anti-MRSA peptides based on database filtering technology.
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DOI：
10.1021/ja305644e
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发表时间：
2012-08-01
影响因子：
15
通讯作者：
Wang G
中科院分区：
文献类型：
--
作者：
Mishra B;Wang G
为了应对全球抗生素耐药性的挑战，必须开发新一代抗菌药。这项交流展示了抗甲氧西林耐药金黄色葡萄球菌(MRSA)的强效多肽的从头算设计。我们的想法是，当在设计的每一步中使用最可能的参数时，多肽很可能是活性的。通过开发数据库过滤技术(DFT)，我们从抗菌肽数据库中获得了最可能的参数(如氨基酸组成、多肽疏水性含量和净电荷)。与传统的阳离子抗菌肽不同，DFTamP1是利用该技术设计的第一个抗MRSA多肽，它是一种疏水性较高但阳离子活性较低的短肽。这样的分子设计使多肽具有很高的效力。事实上，这种多肽造成了细菌表面的破坏，并在60分钟内杀死了社区相关的MRSA USA300。核磁共振波谱对DFTamP1的结构测定表明，DFTamP1具有广泛的疏水表面，这为其对抗MRSA的效力提供了基础，已知的是在表面部署正电荷部分作为一种耐药机制。我们的从头设计与数据库筛选的结合导致了另一种具有增强效力的多肽。由于组成简单、长度短、对酶的稳定性和膜靶向性，所设计的多肽是开发新型抗MRSA药物的有吸引力的先导。我们的数据库衍生的设计概念也可以应用于多肽模拟物的设计，以对抗MRSA。
To meet the challenge of antibiotic resistance worldwide, a new generation of antimicrobials must be developed. This communication demonstrates ab initio design of potent peptides against methicillin-resistant Staphylococcus aureus (MRSA). Our idea is that the peptide is very likely to be active when most probable parameters are utilized in each step of the design. We derived the most probable parameters (e.g. amino acid composition, peptide hydrophobic content, and net charge) from the antimicrobial peptide database by developing a database filtering technology (DFT). Different from classic cationic antimicrobial peptides usually with high cationicity, DFTamP1, the first anti-MRSA peptide designed using this technology, is a short peptide with high hydrophobicity but low cationicity. Such a molecular design made the peptide highly potent. Indeed, the peptide caused bacterial surface damage and killed community-associated MRSA USA300 in 60 minutes. Structural determination of DFTamP1 by NMR spectroscopy revealed a broad hydrophobic surface, providing a basis for its potency against MRSA known to deploy positively charged moieties on the surface as a mechanism for resistance. A combination of our ab initio design with database screening led to yet another peptide with enhanced potency. Because of simple composition, short length, stability to proteases, and membrane targeting, the designed peptides are attractive leads for developing novel anti-MRSA therapeutics. Our database-derived design concept can be applied to the design of peptide mimicries to combat MRSA as well.