Discovery of human cell selective effector molecules using single cell multiplexed activity metabolomics.

Area of Science:

• Metabolomics
• Microbial biochemistry
• Cancer biology

Background:

• Identifying bioactive metabolites with specific cellular activities is difficult due to limited prior knowledge.
• Untargeted metabolomic inventories lack defined cell-targeting properties.

Purpose of the Study:

• To develop a platform for discovering novel microbial metabolites with cell-type-selective effector functions.
• To identify specific metabolite activities against acute myeloid leukemia (AML) cells and other immune cells.

Main Methods:

• Utilized single-cell response profiles and primary human tissues for metabolite screening.
• Employed untargeted metabolomic inventories to identify potential bioactive compounds.
• Tested arrayed metabolites against acute myeloid leukemia patient bone marrow samples.
• Confirmed response mechanisms using high-resolution cell profiling via mass cytometry.

Main Results:

• Discovered microbial metabolites with diverse effector mechanisms, including targeting protein synthesis, cell cycle, DNA repair, and cell death pathways.
• Identified cell-targeting polyketides from prolific bacteria, including a novel leukemia blast-targeting anthracycline.
• Revealed a polyene macrolactam that selectively targets leukemia blasts or nonmalignant cells based on light-triggered isomerization.

Conclusions:

• A novel response platform enables the discovery of microbial metabolites with cell-type-selective activities.
• Specific metabolites demonstrate targeted effects against acute myeloid leukemia cells and distinct immune cell subsets.
• Findings pave the way for developing targeted therapies based on microbial-derived compounds.