Metabolomics for Determining Mechanism of Action of Botanical Medicines

PROJECT SUMMARY
The effectiveness of botanical medical therapies has been observed for centuries and has served as a source
of inspiration for modern medical practice, with 25% of prescribed pharmaceuticals derived from botanicals. Yet,
understanding of the complex chemical interactions and mechanisms of action of botanical natural products has
remained a challenge for the scientific community. With advanced analytical chemistry instrumentation and
access to systems designed for processing large datasets, we are poised to develop a metabolomics tool to
predict mechanism of action of complex botanical extracts to addresses this knowledge gap. To develop this
model, we will evaluate activity of botanical natural products against highly-drug resistant Acinetobacter
baumannii, a common bacterial pathogen. The botanicals tested will include Viola odorata, which is known to
produce antimicrobial cyclic peptides, as well as a series of other botanicals with reported activity against A.
baumannii. Activity of the botanicals will be compared with that of known antibiotics and pure compounds of
botanical origin. Development of a metabolomics-based mechanism of action prediction approach with be the
first goal of this project, while the second goal will be comparison of the mechanism of action demonstrated by
a complex botanical extract to its known constituents. Botanicals displaying a mechanism of action different than
its known constituents, as informed by the metabolomics approach, will be candidates for isolation and
characterization of the combination effects. Finally, a previously established in vivo model using Galleria
mellonella will be employed to predict the cytotoxicity of the botanical natural products. We expect that the
findings of this study will be of benefit to other investigators studying mechanisms of action for complex botanical
natural products and will not be limited to antimicrobial applications. The proposed research is relevant to the
National Center for Complementary and Integrative Health (NCCIH) strategic plan because it involves the
investigation of alterative and complementary health practices common in the US. These studies will be
conducted by a highly qualified trainee (Heather Winter) who seeks to pursue a career in biomedical research.
She has already established a track record for successful research in natural products, and will benefit from the
proposed training plan by expanding her experience with mass spectrometry based metabolomics
methodologies and by gaining experience characterizing complex botanicals. The mentor, Dr. Nadja Cech, is
Patricia A. Sullivan Professor of Chemistry at the University of North Carolina Greensboro, and has effectively
mentored multiple PhD students, including trainees supported by the F31 and T32 fellowships.