发帖
雷达卡
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.
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