新型硫肽类抗生素多糖基化诺卡沙星的挖掘

Discovery of a Novel Multi-glycosylated Nocathiacin using Genome Mining

诺卡沙星是一种由诺卡氏菌Nocardia sp.ATCC 202099产生的e系列硫肽类抗生素,对多种革兰氏阳性菌及其耐药株均具有超强的抗菌活性,且抗菌机制和靶点新颖。但是,结构稳定性差限制了诺卡沙星的成药开发,致使其至今未能临床应用。为克服诺卡沙星的稳定性难题,本研究以诺卡沙星合成的前体肽NocM为探针挖掘锁定了含多糖基模块的诺卡沙星产生菌Actinokineospora fastidiosa JCM 3276。该菌株发酵后产生了一种高分子量的诺卡沙星类似物,经鉴定其为全新结构的四糖基化诺卡沙星(NOC-FG)。与诺卡沙星相比,NOC-FG的稳定性显著提升,且体外抗菌活性相当(MIC_(50):0.0156~0.03125μg/mL),有望成为新型硫肽类抗生素开发的先导化合物。

Nocathiacin(NOC)is a thiopeptide antibiotic belonging to the e-series.It possesses strong antibacterial activity via a novel mechanism against a variety of Gram-positive pathogens,including antibiotic-resistant strains.However,the poor structural stability of NOC limits its development as a clinically applied,commercial drug.To solve this problem,the NocM gene of the biosynthetic gene cluster(BGC)of Nocardia sp.ATCC 202099 was used as a probe to identify a NOC-like BGC in Actinokineospora fastidiosa JCM 3276,which contains a novel sugar biosynthetic module for the production of active donor.After fermentation and analysis,it was found that A.fastidiosa JCM 3276 could biosynthesize an antibacterial compound with a molecular weight higher than NOC,which was identified as a new NOC analogue called NOC-FG.It contains 4 sugar moieties with different linkages.Compared to NOC,NOC-FG displayed improved structural stability without losing in vitro activity toward Gram-positives(MIC_(50):0.0156~0.03125μg/mL).Thus,NOC-FG was considered as a suitable leading compound for the development of novel thiopeptide antibiotics.