Discovery of human cell selective effector molecules using single cell multiplexed activity metabolomics.
Discovery of human cell selective effector molecules using single cell multiplexed activity metabolomics.
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DOI：
10.1038/s41467-017-02470-8
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发表时间：
2018-01-02
影响因子：
16.6
通讯作者：
Bachmann BO
中科院分区：
文献类型：
--
作者：
Earl DC;Ferrell PB Jr;Leelatian N;Froese JT;Reisman BJ;Irish JM;Bachmann BO
在代谢组中发现生物活性代谢物是具有挑战性的，因为通常很少有代谢物分子和细胞靶向活性的预知。在这里，单细胞反应谱和原代人体组织构成了一个反应平台，用于在非靶向代谢组学库存中发现具有细胞类型选择性效应子特性的新型微生物代谢物。Metabolism显示多种效应机制，包括靶向蛋白质合成、细胞周期状态、DNA损伤修复、坏死、凋亡或磷蛋白信号传导。针对急性髓性白血病患者骨髓测试阵列代谢物，并揭示在相同组织活检中特异性靶向母细胞或非白血病免疫细胞亚群的分子。在生物合成多产细菌的提取物中鉴定了细胞靶向聚酮化合物，包括以前未报道的白血病原始细胞靶向蒽环类药物和多烯大环内酰胺，其通过光引发的光化学异构化在靶向原始细胞或非恶性细胞之间交替。采用质谱细胞仪进行的高分辨率细胞分析证实了反应机制，并用于验证初步观察结果。来自植物和微生物提取物的生物活性代谢物具有治疗潜力。在这里，作者将联合收割机非靶向代谢组学阵列与基于流式细胞术的单细胞反应谱相结合，并鉴定了AML患者骨髓中具有细胞亚群特异性活性的代谢物。
Discovering bioactive metabolites within a metabolome is challenging because there is generally little foreknowledge of metabolite molecular and cell-targeting activities. Here, single-cell response profiles and primary human tissue comprise a response platform used to discover novel microbial metabolites with cell-type-selective effector properties in untargeted metabolomic inventories. Metabolites display diverse effector mechanisms, including targeting protein synthesis, cell cycle status, DNA damage repair, necrosis, apoptosis, or phosphoprotein signaling. Arrayed metabolites are tested against acute myeloid leukemia patient bone marrow and molecules that specifically targeted blast cells or nonleukemic immune cell subsets within the same tissue biopsy are revealed. Cell-targeting polyketides are identified in extracts from biosynthetically prolific bacteria, including a previously unreported leukemia blast-targeting anthracycline and a polyene macrolactam that alternates between targeting blasts or nonmalignant cells by way of light-triggered photochemical isomerization. High-resolution cell profiling with mass cytometry confirms response mechanisms and is used to validate initial observations. Bioactive metabolites from plant and microbial extracts hold therapeutic potential. Here, the authors combine untargeted metabolomic arrays with flow cytometry-based single cell response profiling and identify metabolites with cell subset-specific activities in the bone marrow from an AML patient.
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影响因子：
2.1
作者：
Du Y;Derewacz DK;Deguire SM;Teske J;Ravel J;Sulikowski GA;Bachmann BO
通讯作者：
Bachmann BO
影响因子：
17.1
作者：
Gaudillière B;Fragiadakis GK;Bruggner RV;Nicolau M;Finck R;Tingle M;Silva J;Ganio EA;Yeh CG;Maloney WJ;Huddleston JI;Goodman SB;Davis MM;Bendall SC;Fantl WJ;Angst MS;Nolan GP
通讯作者：
Nolan GP
影响因子：
3.7
作者：
Ferrell PB Jr;Diggins KE;Polikowsky HG;Mohan SR;Seegmiller AC;Irish JM
通讯作者：
Irish JM
影响因子：
78.5
作者：
Irish, JM;Kotecha, N;Nolan, GP
通讯作者：
Nolan, GP
影响因子：
64.8
作者：
FOTSIS, T;ZHANG, YM;SCHWEIGERER, L
通讯作者：
SCHWEIGERER, L