Department of Chemistry, The Scripps Research Institute, Jupiter, FL, USA.
1] Department of Chemistry, The Scripps Research Institute, Jupiter, FL, USA [2] School of Life Science, Northeast Agricultural University, Harbin, China.
J Antibiot (Tokyo). 2014 Jan;67(1):127-32. doi: 10.1038/ja.2013.50. Epub 2013 May 29.
We have recently isolated tirandamycin (TAM) B from Streptomyces sp. 17944 as a Brugia malayi AsnRS (BmAsnRS) inhibitor that efficiently kills the adult B. malayi parasites and does not exhibit general cytotoxicity to human hepatic cells. We now report (i) the comparison of metabolite profiles of S. sp. 17944 in six different media, (ii) identification of a medium enabling the production of TAM B as essentially the sole metabolite, and with improved titer, and (iii) isolation and structural elucidation of three new TAM congeners. These findings shed new insights into the structure-activity relationship of TAM B as a BmAsnRS inhibitor, highlighting the δ-hydroxymethyl-α,β-epoxyketone moiety as the critical pharmacophore, and should greatly facilitate the production and isolation of sufficient quantities of TAM B for further mechanistic and preclinical studies to advance the candidacy of TAM B as an antifilarial drug lead. The current study also serves as an excellent reminder that traditional medium and fermentation optimization should continue to be very effective in improving metabolite flux and titer.
我们最近从链霉菌 sp. 17944 中分离出替拉霉素（TAM）B，它是一种丝氨酸 tRNA 合成酶（AsnRS）抑制剂，能有效杀死成年丝虫并对人肝细胞没有一般细胞毒性。我们现在报告（i）在六种不同培养基中链霉菌 sp. 17944 的代谢物谱比较，（ii）鉴定出一种能产生 TAM B 作为基本唯一代谢物的培养基，并且提高了产量，和（iii）三种新的 TAM 同系物的分离和结构阐明。这些发现为 TAM B 作为 BmAsnRS 抑制剂的构效关系提供了新的见解，突出了 δ-羟甲基-α,β-环氧酮部分作为关键药效团，这将极大地促进 TAM B 的生产和分离，以获得足够数量的 TAM B 用于进一步的机制和临床前研究，以推进 TAM B 作为杀丝虫药物先导物的候选资格。本研究还很好地提醒人们，传统的培养基和发酵优化仍然非常有效地提高代谢物通量和产量。
