Laboratory of Genetically Encoded Small Molecules , The Rockefeller University , New York , New York 10065 , United States.
J Am Chem Soc. 2019 Mar 6;141(9):3910-3919. doi: 10.1021/jacs.8b12087. Epub 2019 Feb 20.
The growing threat of antibiotic resistance necessitates the discovery of antibiotics that are active against resistant pathogens. Calcium-dependent antibiotics are a small family of structurally diverse acidic lipopeptides assembled by nonribosomal peptide synthetases (NRPSs) that are known to display various modes of action against antibiotic-resistant pathogens. Here we use NRPS adenylation (AD) domain sequencing to guide the identification, recovery, and cloning of the cde biosynthetic gene cluster from a soil metagenome. Heterologous expression of the cde biosynthetic gene cluster led to the production of cadasides A (1) and B (2), a subfamily of acidic lipopeptides that is distinct from previously characterized calcium-dependent antibiotics in terms of both overall structure and acidic residue rich peptide core. The cadasides inhibit the growth of multidrug-resistant Gram-positive pathogens by disrupting cell wall biosynthesis in the presence of high concentrations of calcium. Interestingly, sequencing of AD domains from diverse soils revealed that sequences predicted to arise from cadaside-like gene clusters are predominantly found in soils containing high levels of calcium carbonate.
抗生素耐药性的威胁日益增加，这就需要开发针对耐药病原体的抗生素。钙依赖性抗生素是由非核糖体肽合成酶（NRPS）组装的一个结构多样的酸性脂肽小家族，已知对多种抗生素耐药病原体具有不同的作用模式。在这里，我们使用 NRPS 腺苷酸化（AD）结构域测序来指导从土壤宏基因组中鉴定、回收和克隆 cde 生物合成基因簇。cde 生物合成基因簇的异源表达导致了 cadasides A（1）和 B（2）的产生，这是一个酸性脂肽亚家族，与以前表征的钙依赖性抗生素在整体结构和富含酸性残基的肽核心方面都不同。cadasides 在高浓度钙存在下通过破坏细胞壁生物合成来抑制多药耐药革兰氏阳性病原体的生长。有趣的是，对来自不同土壤的 AD 结构域进行测序表明，预测来自 cadaside 样基因簇的序列主要存在于含有高浓度碳酸钙的土壤中。
