Cadasides, Calcium-Dependent Acidic Lipopeptides from the Soil Metagenome That Are Active against Multidrug-Resistant Bacteria
Cadasides, Calcium-Dependent Acidic Lipopeptides from the Soil Metagenome That Are Active against Multidrug-Resistant Bacteria
复制标题
DOI：
10.1021/jacs.8b12087
复制
发表时间：
2019-03-06
影响因子：
15
通讯作者：
Brady, Sean F.
中科院分区：
文献类型：
--
作者：
Wu, Changsheng;Shang, Zhuo;Brady, Sean F.
抗生素耐药性的威胁越来越大，需要发现对耐药病原体有活性的抗生素。钙依赖性抗生素是由非核糖体肽合成酶（NRPS）组装的结构多样的酸性脂肽的一个小家族，已知其对耐药病原体表现出各种作用模式。在这里，我们使用NRPS腺苷酸化（AD）结构域测序，以指导识别，恢复和克隆的cde生物合成基因簇从土壤宏基因组。cde生物合成基因簇的异源表达导致产生cadasides A（1）和B（2），这是酸性脂肽的一个亚家族，在整体结构和富含酸性残基的肽核心方面与先前表征的钙依赖性抗生素不同。在高浓度钙的存在下，cadasides通过破坏细胞壁生物合成来抑制多重耐药革兰氏阳性病原体的生长。有趣的是，从不同的土壤AD结构域的测序显示，序列预测产生的cadaside样基因簇主要发现在土壤中含有高水平的碳酸钙。
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.