Biosynthesis of ilamycins featuring unusual building blocks and engineered production of enhanced anti-tuberculosis agents.
Biosynthesis of ilamycins featuring unusual building blocks and engineered production of enhanced anti-tuberculosis agents.
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具有不寻常结构单元的伊拉霉素生物合成和增强抗结核药物的工程化生产
DOI：
10.1038/s41467-017-00419-5
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发表时间：
2017-08-30
影响因子：
16.6
通讯作者：
Ju J
中科院分区：
文献类型：
--
作者：
Ma J;Huang H;Xie Y;Liu Z;Zhao J;Zhang C;Jia Y;Zhang Y;Zhang H;Zhang T;Ju J
结核病仍然是世界上最致命的传染病之一，由于严重的耐药性以及结核病/人类免疫缺陷病毒的共流行，迫切需要新型抗结核药物。在这里，我们展示了从深海来源的黑链霉菌 SCSIO ZH16 中分离出的六种抗分枝杆菌伊拉霉素同系物 (1-6)，它们带有稀有的 L-3-硝基-酪氨酸和 L-2-氨基-4-己烯酸结构单元。通过一系列基因失活、前体化学互补、同位素标记的前体喂养实验以及来自各自突变体的三个中间体 (6-8) 的结构阐明，在伊拉霉素生物合成机制中探索了稀有的 L-3-硝基酪氨酸和 L-2-氨基-4-己烯酸单元的生物合成以及三个预剪裁和两个后剪裁步骤。最令人印象深刻的是，伊拉霉素E1/E2是由基因工程突变菌株产生的高滴度，显示出非常有效的抗结核活性，对结核分枝杆菌H37Rv的最低抑制浓度值约为9.8nM，构成极其有效和令人兴奋的抗结核药物先导物。结核病（TB）仍然是世界上最致命的传染病之一，由于严重的耐药性以及结核病/艾滋病毒的共同流行，迫切需要新型抗结核药物。在这里，作者表明，具有不寻常结构单元的抗分枝杆菌伊拉霉素同系物具有极强的抗结核活性。
Tuberculosis remains one of the world’s deadliest communicable diseases, novel anti-tuberculosis 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 anti-mycobacterial 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 anti-tuberculosis activity with an minimum inhibitory concentration value ≈9.8 nM to Mycobacterium tuberculosis H37Rv constituting extremely potent and exciting anti-tuberculosis drug leads. Tuberculosis (TB) remains one of the world’s deadliest communicable diseases, novel anti-TB agents are urgently needed due to severe drug resistance and the co-epidemic of TB/HIV. Here, the authors show that anti-mycobacterial ilamycin congeners bearing unusual structural units possess extremely potent anti-tuberculosis activities.
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影响因子：
14.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Kers, JA;Wach, MJ;Loria, R
通讯作者：
Loria, R
DOI：
10.1513/pats.200402-011ms
发表时间：
2004-01-01
期刊：
Proceedings of the American Thoracic Society
影响因子：
--
作者：
Kharitonov, Sergei A;Barnes, Peter J
通讯作者：
Barnes, Peter J
DOI：
10.1073/pnas.0337542100
发表时间：
2003-02-18
影响因子：
11.1
作者：
Gust, B;Challis, GL;Chater, KF
通讯作者：
Chater, KF
影响因子：
3.5
作者：
CARY, LW;TAKITA, T;OHNISHI, M
通讯作者：
OHNISHI, M