Genome-Directed Lead Discovery: Biosynthesis, Structure Elucidation, and Biological Evaluation of Two Families of Polyene Macrolactams against Trypanosoma brucei.
Genome-Directed Lead Discovery: Biosynthesis, Structure Elucidation, and Biological Evaluation of Two Families of Polyene Macrolactams against Trypanosoma brucei.
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DOI：
10.1021/acschembio.5b00308
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发表时间：
2015-10-16
影响因子：
4
通讯作者：
Linington RG
中科院分区：
文献类型：
--
作者：
Schulze CJ;Donia MS;Siqueira-Neto JL;Ray D;Raskatov JA;Green RE;McKerrow JH;Fischbach MA;Linington RG
海洋天然产物是对抗许多病原体的先导化合物的重要来源。在此，我们报告了从海洋放线菌小单孢菌中发现的lobosamides A-C，代表细菌产生的多烯大环内酰胺的小但不断增长的家族的三个新成员。Lobosamide对原生动物寄生虫布氏锥虫（Lobosamide A IC 50 = 0.8 μM）（人类非洲锥虫（HAT）的病原体）具有生长抑制活性。的lobosamides的生物合成基因簇进行测序和组装，并建议之间的26元大环内酰胺保守的簇组织。虽然缺乏对该家族许多成员的相对和绝对构型的测定，但使用化学修饰、详细的光谱分析和生物信息学的组合来推断lobosamides的绝对构型。我们实施了一种“分子-基因-分子”的方法来确定其他细菌中类似簇的流行率，这导致了从放射丝藻中发现了另外两种大环内酰胺，mirilactams A和B。这些额外的类似物，使我们能够确定特定的结构活性关系，有助于这一类的抗锥虫活性。这种方法说明了化学分析和基因组学相结合的力量，在发现和表征的天然产物作为新的先导化合物被忽视的疾病的目标。
Marine natural products are an important source of lead compounds against many pathogenic targets. Herein, we report the discovery of lobosamides A-C from a marine actinobacterium Micromonospora sp., representing three new members of a small but growing family of bacterially produced polyene macrolactams. The lobosamides display growth inhibitory activity against the protozoan parasite Trypanosoma brucei (Lobosamide A IC50 = 0.8 μM), the causative agent of human African trypanosomiasis (HAT). The biosynthetic gene cluster of the lobosamides was sequenced and assembled and suggests a conserved cluster organization amongst the 26-membered macrolactams. While determination of the relative and absolute configurations of many members of this family is lacking, the absolute configurations of the lobosamides were deduced using a combination of chemical modification, detailed spectroscopic analysis, and bioinformatics. We implemented a “molecules-to-genes-to-molecules” approach to determine the prevalence of similar clusters in other bacteria, which led to the discovery of two additional macrolactams, mirilactams A and B from Actinosynnema mirum. These additional analogs have allowed us to identify specific structure activity relationships that contribute to the antitrypanosomal activity of this class. This approach illustrates the power of combining chemical analysis and genomics in the discovery and characterization of natural products as new lead compounds for neglected disease targets.
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影响因子：
16.6
作者：
Janssen, Dominic;Albert, Dieter;Kalesse, Markus
通讯作者：
Kalesse, Markus
影响因子：
4.2
作者：
Rodenko, Boris;Al-Salabi, Mohammed I.;de Koning, Harry P.
通讯作者：
de Koning, Harry P.
影响因子：
14.9
作者：
Blin K;Medema MH;Kazempour D;Fischbach MA;Breitling R;Takano E;Weber T
通讯作者：
Weber T
影响因子：
5.1
作者：
Giessen, Tobias W.;Franke, Kamila B.;Marahiel, Mohamed A.
通讯作者：
Marahiel, Mohamed A.
影响因子：
3.4
作者：
Koukalova, Alena;Pokorna, Sarka;Hof, Martin
通讯作者：
Hof, Martin