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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Combinatorial biosynthesis of novel antibiotics related to daptomycin
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Combinatorial biosynthesis of novel antibiotics related to daptomycin

机译：与达托霉素有关的新型抗生素的组合生物合成

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摘要

Daptomycin, a cyclic lipopeptide produced by Streptomyces roseosporus, is the active ingredient of Cubicin (daptomycin-for-injection), a first-in-class antibiotic approved for treatment of skin and skin-structure infections caused by Gram-positive pathogens and bacteremia and endocarditis caused by Staphylococcus aureus, including methicillin-resistant strains. Genetic engineering of the nonribosomal peptide synthetase (NRPS) in the daptomycin biosynthetic pathway was exploited for the biosynthesis of novel active antibiotics. A-Red-mediated recombination was used to exchange single or multiple modules in the DptBC subunit of the NRPS to modify the daptomycin cyclic peptide core. We combined module exchanges, NRPS subunit exchanges, inactivation of the tailoring enzyme glutamic acid 3-methyltransferase, and natural variations of the lipid tail to generate a library of novel lipopeptides, some of which were as active as daptomycin against Gram-positive bacteria. One compound was more potent against an Escherichia coli imp mutant that has increased outer membrane permeability. This study established a robust combinatorial biosynthesis platform to produce novel peptide antibiotics in sufficient quantities for antimicrobial screening and drug development.
机译：达托霉素是由玫瑰链霉菌产生的一种环状脂肽，是立方霉素（注射用达托霉素）的活性成分，该药物是一流的抗生素，被批准用于治疗由革兰氏阳性病原体和菌血症引起的皮肤和皮肤结构感染。由金黄色葡萄球菌引起的心内膜炎，包括耐甲氧西林的菌株。达托霉素生物合成途径中非核糖体肽合成酶（NRPS）的基因工程被开发用于新型活性抗生素的生物合成。使用A-Red介导的重组来交换NRPS的DptBC亚基中的单个或多个模块，以修饰达托霉素环肽核心。我们结合了模块交换，NRPS亚基交换，定制酶谷氨酸3-甲基转移酶的失活以及脂质尾巴的自然变异，生成了新的脂肽文库，其中一些与达托霉素一样对革兰氏阳性细菌具有活性。一种化合物对具有增加的外膜通透性的大肠杆菌imp突变体更有效。这项研究建立了一个强大的组合生物合成平台，可以生产足够数量的新型肽类抗生素用于抗菌药物筛选和药物开发。

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