题目: Biosynthesis of ilamycins featuring unusual building blocks and engineered production of enhanced anti-tuberculosis agents

作者: Junying Ma*, Hongbo Huang, Yunchang Xie, Zhiyong Liu, Jin Zhao, Chunyan Zhang, Yanxi Jia, Yun Zhang, Hua Zhang, Tianyu Zhang, Jianhua Ju*

刊物: Nature Communications

年卷期页: 2017,8(1):391

摘要：Tuberculosis remains one of the world’s deadliest communicable diseases, novel antituberculosis agents are urgently needed due to severe drug resistance and the co-epidemic of tuberculosis/human immunodeficiency virus. Here, we show the isolation of six antimycobacterial ilamycin congeners (1–6) bearing rare L-3-nitro-tyrosine and L-2-amino-4-hexenoic acid structural units from the deep sea-derived Streptomyces atratus SCSIO ZH16. The biosynthesis of the rare L-3-nitrotyrosine and L-2-amino-4-hexenoic acid units as well as three pre-tailoring and two post-tailoring steps are probed in the ilamycin biosynthetic machinery through a series of gene inactivation, precursor chemical complementation, isotope-labeled precursor feeding experiments, as well as structural elucidation of three intermediates (6–8) from the respective mutants. Most impressively, ilamycins E1/E2, which are produced in high titers by a genetically engineered mutant strain, show very potent antituberculosis activity with an minimum inhibitory concentration value ≈9.8 nM to Mycobacterium tuberculosis H37Rv constituting extremely potent and exciting anti-tuberculosis drug leads.