The Scripps Research Institute, d/b/a Calibr, a division of Scripps Research, La Jolla, CA 92037, USA.
Chem Commun (Camb). 2019 Feb 12;55(14):2007-2014. doi: 10.1039/c8cc09961h.
Antibiotic resistance in bacteria has become a serious threat to public health, and therefore there is an urgent need to develop new classes of antimicrobial agents. Nowadays, natural antimicrobial peptides (AMPs) and their synthetic derivatives are considered as promising alternatives to traditional antibiotics. The broad molecular diversity of AMPs, in terms of sequences and structures, suggests that their activity does not depend on specific features of amino acid sequence or peptide conformation. We therefore selected two common properties of AMPs, (high percentage of hydrophobic and cationic amino acids), to develop a novel approach to synthesize random antimicrobial peptide mixtures (RPMs). Instead of incorporating a single amino acid at each coupling step, a mixture of hydrophobic and cationic amino acids in a defined proportion is coupled. This results in a mixture that contains up to 2n sequences, where n is the number of the coupling step, of random peptides with a defined composition, stereochemistry, and controlled chain length. We have discovered that RPMs of hydrophobic and cationic α-amino acids, such as phenylalanine and lysine, display strong and broad antimicrobial activity towards Gram-negative, Gram-positive, clinically isolated antibiotic resistant "superbugs", and several plant pathogenic bacteria. This review summarizes our efforts to explore the mode of action of RPMs and their potential as bioactive agents for multiple applications, including the prevention of biofilm formation and degradation of mature biofilm (related to human health), reduction of disease severity in plant bacterial disease models (related to crop protection), and inhibition of bacterial growth in milk (related to food preservation). All our findings illustrate the effectiveness of RPMs and their great potential for various applications.
细菌的抗生素耐药性已对公共健康构成严重威胁，因此急需开发新类别的抗菌药物。如今，天然抗菌肽 (AMPs) 及其合成衍生物被认为是传统抗生素的有前途的替代品。AMPs 在序列和结构方面具有广泛的分子多样性，这表明它们的活性不依赖于氨基酸序列或肽构象的特定特征。因此，我们选择了 AMP 的两个常见特性（高比例的疏水性和阳离子性氨基酸），开发了一种合成随机抗菌肽混合物 (RPM) 的新方法。不是在每个偶联步骤中都掺入单个氨基酸，而是以特定比例混合疏水性和阳离子性氨基酸。这导致混合物中包含多达 2n 个序列，其中 n 是偶联步骤的数量，是具有特定组成、立体化学和受控链长的随机肽的混合物。我们发现疏水性和阳离子性α-氨基酸（如苯丙氨酸和赖氨酸）的 RPM 对革兰氏阴性、革兰氏阳性、临床分离的抗生素耐药“超级细菌”以及几种植物病原菌具有强大而广泛的抗菌活性。本综述总结了我们探索 RPM 作用模式及其作为多种应用（包括生物膜形成的预防和成熟生物膜的降解（与人类健康有关）、植物细菌疾病模型中疾病严重程度的降低（与作物保护有关）以及抑制牛奶中的细菌生长（与食品保存有关）的生物活性剂的潜力的努力。我们所有的发现都说明了 RPM 的有效性及其在各种应用中的巨大潜力。
