Identification of novel mureidomycin analogues via rational activation of a cryptic gene cluster in Streptomyces roseosporus NRRL 15998.
Identification of novel mureidomycin analogues via rational activation of a cryptic gene cluster in Streptomyces roseosporus NRRL 15998.
复制标题
通过合理激活玫瑰孢链霉菌 NRRL 15998 中的隐秘基因簇鉴定新型穆里霉素类似物
DOI：
10.1038/srep14111
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发表时间：
2015-09-15
影响因子：
4.6
通讯作者：
Niu G
中科院分区：
文献类型：
--
作者：
Jiang L;Wang L;Zhang J;Liu H;Hong B;Tan H;Niu G
迫切需要抗菌剂来应对日益增长的耐药病原体威胁。新型抗菌剂的一个重要来源是嵌入微生物基因组中的大量隐藏基因簇。基因组挖掘揭示了玫瑰孢链霉菌NRRL 15998染色体上的一个萘莎霉素/脲霉素生物合成基因簇。通过组成型表达来自链霉菌SS菌株sansanmycin生物合成基因簇的外源激活基因ssaA来激活隐藏基因簇。通过对关键生物合成基因的RT-PCR分析验证了基因簇的表达。活化的代谢产物表现出对高度难治性病原体铜绿假单胞菌的有效抑制活性，并且代谢产物的表征导致发现八种乙酰化的脲霉素类似物。令人惊讶的是，天然激活基因SSGG_02995，一个ssaA同源物在S. roseosporus NRRL 15998对脲霉素刺激没有有益作用。该研究为获得新型抗生素提供了一条新的途径，并将促进链霉菌中大量天然产物的开发。
Antimicrobial agents are urgently needed to tackle the growing threat of antibiotic-resistant pathogens. An important source of new antimicrobials is the large repertoire of cryptic gene clusters embedded in microbial genomes. Genome mining revealed a napsamycin/mureidomycin biosynthetic gene cluster in the chromosome of Streptomyces roseosporus NRRL 15998. The cryptic gene cluster was activated by constitutive expression of a foreign activator gene ssaA from sansanmycin biosynthetic gene cluster of Streptomyces sp. strain SS. Expression of the gene cluster was verified by RT-PCR analysis of key biosynthetic genes. The activated metabolites demonstrated potent inhibitory activity against the highly refractory pathogen Pseudomonas aeruginosa and characterization of the metabolites led to the discovery of eight acetylated mureidomycin analogues. To our surprise, constitutive expression of the native activator gene SSGG_02995, a ssaA homologue in S. roseosporus NRRL 15998, has no beneficial effect on mureidomycin stimulation. This study provides a new way to activate cryptic gene cluster for the acquisition of novel antibiotics and will accelerate the exploitation of prodigious natural products in Streptomyces.