期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-017-00419-5
关键词
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资金
- NSFC [31270134, 81425022, U1501223, 81572037]
- CAS [XDA11030403, YIPA-2013226, 154144KYSB20150045]
- Guangdong NSF [2016A030312014, 2016A030310123]
- Pearl River S&T Nova Program of Guangzhou, China [2014J2200089]
- Guangzhou Healthcare and Cooperative Innavation Major Project [201508020248, 201604020019]
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 approximate to 9.8 nM to Mycobacterium tuberculosis H37Rv constituting extremely potent and exciting anti-tuberculosis drug leads.
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