Coculture of Marine Invertebrate-Associated Bacteria and Interdisciplinary Technologies Enable Biosynthesis and Discovery of a New Antibiotic, Keyicin.
Coculture of Marine Invertebrate-Associated Bacteria and Interdisciplinary Technologies Enable Biosynthesis and Discovery of a New Antibiotic, Keyicin.
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DOI：
10.1021/acschembio.7b00688
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发表时间：
2017-12-15
影响因子：
4
通讯作者：
Bugni TS
中科院分区：
文献类型：
--
作者：
Adnani N;Chevrette MG;Adibhatla SN;Zhang F;Yu Q;Braun DR;Nelson J;Simpkins SW;McDonald BR;Myers CL;Piotrowski JS;Thompson CJ;Currie CR;Li L;Rajski SR;Bugni TS
近年来，基因组学和代谢组学的进展清楚地表明，地球上微生物的生物合成能力远远超过了以前的预期。这部分归因于认识到大多数微生物天然产物（NP）生产者具有不易于经受经典实验室发酵条件的生物合成机器。这种“隐藏的”或休眠的生物合成基因簇（BGC）编码大量潜在的新抗生素，因此，在受控的实验室条件下，已经成为非常有吸引力的激活靶点。我们在这里报告，红球菌属和小单孢菌属的共培养提供keyicin，一种新的，否则无法实现的双-硝基糖基化蒽环类抗生素的作用机制（MOA）似乎偏离其他蒽环类抗生素。利用高分辨率MS和NMR技术以及详细的分子模拟研究阐明了keyicin的结构。测序的keyicin BGC（小单孢菌基因组内），使结构和基因组的比较，以其他蒽环类药物生产系统，通知努力表征keyicin。新的NP被发现对革兰氏阳性细菌包括红球菌属和分枝杆菌属具有选择性活性。基于大肠杆菌的化学基因组学研究表明，与许多其他蒽环类药物相比，keyicin的MOA不会引起核酸损伤。
Advances in genomics and metabolomics have made clear in recent years that microbial biosynthetic capacities on Earth far exceed previous expectations. This is attributable, in part, to the realization that most microbial natural product (NP) producers harbor biosynthetic machineries not readily amenable to classical laboratory fermentation conditions. Such “cryptic” or dormant biosynthetic gene clusters (BGCs) encode for a vast assortment of potentially new antibiotics and, as such, have become extremely attractive targets for activation under controlled laboratory conditions. We report here that co-culturing of a Rhodococcus sp. and a Micromonospora sp. affords keyicin, a new and otherwise unattainable bis-nitroglycosylated anthracycline whose mechanism of action (MOA) appears to deviate from those of other anthracyclines. The structure of keyicin was elucidated using high resolution MS and NMR technologies, as well as detailed molecular modeling studies. Sequencing of the keyicin BGC (within the Micromonospora genome) enabled both structural and genomic comparisons to other anthracycline-producing systems informing efforts to characterize keyicin. The new NP was found to be selectively active against Gram-positive bacteria including both Rhodococcus sp. and Mycobacterium sp. E. coli-based chemical genomics studies revealed that keyicin’s MOA, in contrast to many other anthracyclines, does not invoke nucleic acid damage.
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影响因子：
14.9
作者：
Kamra P;Gokhale RS;Mohanty D
通讯作者：
Mohanty D
影响因子：
3.3
作者：
KAWAI, H;HAYAKAWA, Y;OTAKE, N
通讯作者：
OTAKE, N
DOI：
10.1128/genomea.01406-16
发表时间：
2016-12-15
期刊：
Genome announcements
影响因子：
--
作者：
Adnani N;Braun DR;McDonald BR;Chevrette MG;Currie CR;Bugni TS
通讯作者：
Bugni TS
影响因子：
--
作者：
Duncan KR;Crüsemann M;Lechner A;Sarkar A;Li J;Ziemert N;Wang M;Bandeira N;Moore BS;Dorrestein PC;Jensen PR
通讯作者：
Jensen PR
影响因子：
16.6
作者：
Barkal LJ;Theberge AB;Guo CJ;Spraker J;Rappert L;Berthier J;Brakke KA;Wang CCC;Beebe DJ;Keller NP;Berthier E
通讯作者：
Berthier E