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Open AccessArticle

An Isotopic Ratio Outlier Analysis Approach for Global Metabolomics of Biosynthetically Talented Actinomycetes

1
Chemistry Department, University of North Florida, Jacksonville, FL 32224, USA
2
IROA Technologies, Ann Arbor, MI 48105, USA
*
Author to whom correspondence should be addressed.
Metabolites 2019, 9(9), 181; https://doi.org/10.3390/metabo9090181
Received: 1 September 2019 / Accepted: 4 September 2019 / Published: 10 September 2019
(This article belongs to the Special Issue Natural Products Metabolomics)
Actinomycetes are powerhouses of natural product biosynthesis. Full realization of this biosynthetic potential requires approaches for recognizing novel metabolites and determining mediators of metabolite production. Herein, we develop an isotopic ratio outlier analysis (IROA) ultra-high performance liquid chromatography-mass spectrometry (UHPLC/MS) global metabolomics strategy for actinomycetes that facilitates recognition of novel metabolites and evaluation of production mediators. We demonstrate this approach by determining impacts of the iron chelator 2,2′-bipyridyl on the Nocardiopsis dassonvillei metabolome. Experimental and control cultures produced metabolites with isotopic carbon signatures that were distinct from corresponding “standard” culture metabolites, which were used as internal standards for LC/MS. This provided an isotopic MS peak pair for each metabolite, which revealed the number of carbon atoms and relative concentrations of metabolites and distinguished biosynthetic products from artifacts. Principal component analysis (PCA) and random forest (RF) differentiated bipyridyl-treated samples from controls. RF mean decrease accuracy (MDA) values supported perturbation of metabolites from multiple amino acid pathways and novel natural products. Evaluation of bipyridyl impacts on the nocazine/XR334 diketopiperazine (DKP) pathway revealed upregulation of amino acid precursors and downregulation of late stage intermediates and products. These results establish IROA as a tool in the actinomycete natural product chemistry arsenal and support broad metabolic consequences of bipyridyl. View Full-Text
Keywords: natural product; secondary metabolite; actinomycete; isotopic ratio outlier analysis; global metabolomics; diketopiperazine; liquid chromatography-mass spectrometry; siderophore natural product; secondary metabolite; actinomycete; isotopic ratio outlier analysis; global metabolomics; diketopiperazine; liquid chromatography-mass spectrometry; siderophore
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Carey, J.; Nguyen, T.; Korchak, J.; Beecher, C.; de Jong, F.; Lane, A.L. An Isotopic Ratio Outlier Analysis Approach for Global Metabolomics of Biosynthetically Talented Actinomycetes. Metabolites 2019, 9, 181.

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