Stable Isotope-Guided Metabolomics Reveals Polar-Functionalized Fatty-Acylated RiPPs from <i>Streptomyces</i>
Stable Isotope-Guided Metabolomics Reveals Polar-Functionalized Fatty-Acylated RiPPs from <i>Streptomyces</i>
复制标题
稳定同位素引导的代谢组学揭示了来自链霉菌的极性功能化脂肪酰化 RiPP
DOI：
10.1021/acschembio.2c00601
复制
发表时间：
2022
影响因子：
4
通讯作者：
Onaka Hiroyasu
中科院分区：
文献类型：
--
作者：
Asamizu Shumpei;Ijichi Shinta;Hoshino Shotaro;Jo Hansaem;Takahashi Hidenori;Itoh Yuko;Matsumoto Sohkichi;Onaka Hiroyasu
具有极性功能化脂肪酰基的核糖体合成和翻译后修饰肽（RiPPs）是一种罕见的未开发的天然产物。尽管极性功能化脂肪酰化ripp （pfar）具有抗菌潜力，但其应用范围仍然有限。因此，扩大化学空间有望促进药剂的发展。在这项研究中，我们通过基因组挖掘和稳定同位素引导的比较代谢组学来发现新的PFAR天然产物。我们重点研究了PFARs将精氨酸或赖氨酸作为脂肪酰基的起始单位，并将13c6, 15n4 -l-精氨酸或13c6, 15n2 -l-赖氨酸添加到细菌培养中的特征。提取代谢物，并与未标记精氨酸或赖氨酸的培养物进行比较。我们从lydicusstreptomyces nbrc 13 058中成功分离出solabiomycin A和B，从streptomyces nigrescensHEK616中分离出alopeptin B，它们在labionin部分含有一个亚氧基。基因破坏实验表明，sols编码一种推测为黄素腺嘌呤二核苷酸(FAD) -烟酰胺腺嘌呤二核苷酸（磷酸）（NAD(P)）结合蛋白，参与芳基硫化物的亚砜化。索拉比霉素对革兰氏阳性菌（包括结核分枝杆菌ish37rv）均有抑菌活性，最低95%抑制浓度（MIC95）为3.125 μg/mL，提示其具有抗结核潜力。
Ribosomally synthesized and posttranslationally modified peptides (RiPPs) with polar-functionalized fatty acyl groups are a rarely found untapped class of natural products. Although polar-functionalized fatty-acylated RiPPs (PFARs) have potential as antimicrobial agents, the repertoire is still limited. Therefore, expanding the chemical space is expected to contribute to the development of pharmaceutical agents. In this study, we performed genome mining and stable isotope-guided comparative metabolomics to discover new PFAR natural products. We focused on the feature that PFARs incorporatel-arginine orl-lysine as the starter unit of the fatty acyl group and fed13C6,15N4-l-arginine or13C6,15N2-l-lysine to bacterial cultures. Metabolites were extracted and compared with those extracted from nonlabeledl-arginine orl-lysine fed cultures. We identified putative PFARs and successfully isolated solabiomycin A and B fromStreptomyces lydicusNBRC 13 058 and albopeptin B fromStreptomyces nigrescensHEK616, which contained a sulfoxide group in the labionin moiety. The gene disruption experiment indicated thatsolS, which encodes a putative flavin adenine dinucleotide (FAD)–nicotinamide adenine dinucleotide (phosphate) (NAD(P))-binding protein, is involved in the sulfoxidation of aryl sulfides. The solabiomycins showed antibacterial activity against Gram-positive bacteria, includingMycobacterium tuberculosisH37Rv with a minimum 95% inhibitory concentration (MIC95) of 3.125 μg/mL, suggesting their potential as antituberculosis agents.