Suroto Dian Anggraini, Kitani Shigeru, Miyamoto Kiyoko T, Sakihama Yasuko, Arai Masayoshi, Ikeda Haruo, Nihira Takuya
International Center for Biotechnology, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Research Faculty of Agriculture, Hokkaido University, Sapporo 060-8589, Japan.
J Biosci Bioeng. 2017 Dec;124(6):611-617. doi: 10.1016/j.jbiosc.2017.06.014. Epub 2017 Jul 17.
The genomes of actinomycetes encode many cryptic novel/useful bioactive compounds, but access to these cryptic secondary metabolites remains limited. Streptomyces avermitilis predominantly produces three polyketide antibiotics (avermectin, filipin, and oligomycin) but has the potential to produce more secondary metabolites based on the number of cryptic biosynthetic gene clusters. Here, we extensively investigated the metabolite profiles of a gene disruptant of AvaR3 (an autoregulator receptor homologue), which is involved in the pleiotropic regulation of antibiotic production and cell morphology. Unlike the wild-type strain, the avaR3 mutant accumulated compound 3 in the culture. The chemical structure of compound 3 was elucidated on the basis of various spectroscopic analyses, and was identified as phthoxazolin A, a cellulose synthesis inhibitor. Bioassays demonstrated that compound 3 exerts growth inhibitory activity against a broad range of plant pathogenic oomycetes. Moreover, unlike avermectin production, phthoxazolin A (3) production was negatively controlled by avenolide, a new type of autoregulator in streptomycetes, through the function of AvaR3. These results suggest that the genetic manipulation of autoregulator receptor homologues would be a valuable tool for the discovery of cryptic bioactive compounds.
放线菌的基因组编码了许多隐秘的新型/有用的生物活性化合物，但获取这些隐秘的次级代谢产物仍然有限。阿维链霉菌主要产生三种聚酮类抗生素（阿维菌素、菲律宾菌素和寡霉素），但基于隐秘生物合成基因簇的数量，它有产生更多次级代谢产物的潜力。在这里，我们广泛研究了AvaR3（一种自调控受体同源物）基因破坏株的代谢产物谱，AvaR3参与抗生素生产和细胞形态的多效性调控。与野生型菌株不同，avaR3突变体在培养物中积累了化合物3。基于各种光谱分析阐明了化合物3的化学结构，并将其鉴定为邻苯恶唑啉A，一种纤维素合成抑制剂。生物测定表明，化合物3对多种植物致病卵菌具有生长抑制活性。此外，与阿维菌素的产生不同，邻苯恶唑啉A（3）的产生受到链霉菌中一种新型自调控因子avenolide通过AvaR3功能的负调控。这些结果表明，自调控受体同源物的基因操作将是发现隐秘生物活性化合物的有价值工具。
