Complexity, synergy, endophytes and more: Addressing the challenges of botanical medicine research

Researchers studying botanical medicines constantly battle the challenge of distilling complex mixtures down to bioactive compounds. The gold standard approach towards this goal is bioassay-guided fractionation, in which the mixture is subjected to successive rounds of purification and bioassays until an active compound is identified. For complex botanical extracts, however, bioassay guided fractionation is often fraught with challenges. The process is biased towards the most abundant mixture components, which may not be the most biologically active. Furthermore, if multiple compounds contribute either additively, antagonistically, or synergistically to the observed biological activity of the mixture, activity may be lost upon isolation. Finally, mixture composition can vary widely depending on myriad conditions, including both growth conditions for the plant and its association with environmental microbes.

The focus of this presentation will be on the application of untargeted metabolomics strategies to address some of the aforementioned challenges. Our laboratory has employed metabolomics as a tool to identify biologically active components (including synergists) of mixtures, and to investigate the potential role of endophytes in altering the activity of botanicals. Several case studies will be presented illustriting these applications. In the course of these stuides, our laboratory and others have observed that a major challenge towards the effective application of metabolomics for natural products research is meaningful integration of complex biological and chemical datasets. Some strategies towards overcoming this challenge will be discussed.

Acknowledgements: This work is a collective effort of many outstanding scientists. These include Dr. Nicholas Oberlies, Dr. Huzefa Raja, Dr. Daniel Todd, and Dr. Joshua Kellogg at the University North Carolina Greensboro, Dr. Olav Kvalheim at the University of Bergen in Norway, and Dr. Alexander Horswill at the University of Iowa. Countless undergraduate and graduate students have also made critical contributions. Funding was provided by the National Center for Complementary and Integrative Health, a component of the National Institutes of Health (grant number R01 AT006860).

Keywords: Synergy, Botanical, Endophyte, Metabolomics, Chemometrics,.