Format

Send to

Choose Destination
Nat Commun. 2018 Jan 2;9(1):39. doi: 10.1038/s41467-017-02470-8.

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

Author information

1
Department of Chemistry, Vanderbilt University, 7330 Stevenson Center, Station B 351822, Nashville, TN, 37235, USA.
2
Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, D-3100 Medical Center North, Nashville, TN, 37232, USA.
3
Department of Cell and Developmental Biology, Vanderbilt University, 465 21st Avenue South, Nashville, TN, 37232, USA.
4
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN, 37232, USA.
5
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, 1161 21st Avenue South, D-2220 Medical Center North, Nashville, TN, 37232, USA.
6
Department of Cell and Developmental Biology, Vanderbilt University, 465 21st Avenue South, Nashville, TN, 37232, USA. jonathan.irish@vanderbilt.edu.
7
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN, 37232, USA. jonathan.irish@vanderbilt.edu.
8
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, 1161 21st Avenue South, D-2220 Medical Center North, Nashville, TN, 37232, USA. jonathan.irish@vanderbilt.edu.
9
Department of Chemistry, Vanderbilt University, 7330 Stevenson Center, Station B 351822, Nashville, TN, 37235, USA. brian.bachmann@vanderbilt.edu.

Abstract

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.

PMID:
29295987
PMCID:
PMC5750220
DOI:
10.1038/s41467-017-02470-8
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center