Bacteriocins hold unprecedented promise as a largely untapped source of antibiotic alternatives in the age of multidrug resistance. Here, we describe the first approach to systematically design variants of a novel AS-48 bacteriocin homologue, which we have termed safencin AS-48, from Bacillus safensis, to gain insights into engineering improved activity of bacteriocins. A library of synthetic peptides in which systematic amino acid substitutions to vary the periodicity and abundance of polar, acidic, aliphatic, and hydrophobic residues were generated for a total of 96 novel peptide variants of a single bacteriocin candidate. Using this method, we identified nine synthetic safencin (syn-safencin) variants with broad and potent antimicrobial activities with minimal inhibitory concentrations (MIC) as low as 250 nM against E. coli, P. aeruginosa, X. axonopodis, and S. pyogenes with minimal cytotoxicity to mammalian cells. It is anticipated that the strategies we have developed will serve as general guides for tuning the specificity of a given natural bacteriocin compound for therapeutic specificity.

中文翻译：

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syn-safencin 的合理设计，一种源自环状细菌素 safencin AS-48 的新型线性抗菌肽。

在多重耐药性时代，细菌素作为一种尚未开发的抗生素替代品来源具有前所未有的前景。在这里，我们描述了第一种系统地设计来自 Bacillus safensis 的新型 AS-48 细菌素同源物变体的方法，我们将其称为安全素 AS-48，以深入了解工程改进的细菌素活性。一个合成肽库，其中系统性的氨基酸取代可改变极性、酸性、脂肪族和疏水性残基的周期性和丰度，共产生了 96 个单一候选细菌素的新肽变体。使用这种方法，我们鉴定了九种合成安全素 (syn-safencin) 变体，它们具有广泛而有效的抗菌活性，对大肠杆菌、铜绿假单胞菌、X. axonopodis 和 S. pyogenes 对哺乳动物细胞的细胞毒性最小。预计我们开发的策略将用作调整给定天然细菌素化合物的特异性以实现治疗特异性的一般指南。