Adnani Navid, Chevrette Marc G, Adibhatla Srikar N, Zhang Fan, Yu Qing, Braun Doug R, Nelson Justin, Simpkins Scott W, McDonald Bradon R, Myers Chad L, Piotrowski Jeff S, Thompson Christopher J, Currie Cameron R, Li Lingjun, Rajski Scott R, Bugni Tim S
Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin , Madison, Wisconsin 53705, United States.
Department of Bacteriology, University of Wisconsin , Madison, Wisconsin 53705, United States.
ACS Chem Biol. 2017 Dec 15;12(12):3093-3102. doi: 10.1021/acschembio.7b00688. Epub 2017 Nov 22.
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 coculturing 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.
近年来,基因组学和代谢组学的进展已明确表明,地球上微生物的生物合成能力远远超出了先前的预期。部分原因在于,人们认识到大多数微生物天然产物(NP)生产者拥有的生物合成机制不易适应经典的实验室发酵条件。这类“隐秘”或休眠的生物合成基因簇(BGC)编码了大量潜在的新型抗生素,因此,它们已成为在可控实验室条件下激活的极具吸引力的目标。我们在此报告,红球菌属菌株与小单孢菌属菌株共培养可产生凯西菌素,这是一种新型且无法通过其他方式获得的双氮糖基化蒽环类抗生素,其作用机制(MOA)似乎与其他蒽环类抗生素不同。利用高分辨率质谱和核磁共振技术以及详细的分子建模研究阐明了凯西菌素的结构。对凯西菌素BGC(位于小单孢菌基因组内)进行测序,能够与其他蒽环类抗生素生产系统进行结构和基因组比较,为表征凯西菌素的研究提供信息。发现这种新型NP对包括红球菌属菌株和分枝杆菌属菌株在内的革兰氏阳性菌具有选择性活性。基于大肠杆菌的化学基因组学研究表明,与许多其他蒽环类抗生素不同,凯西菌素的作用机制不会导致核酸损伤。