Microbial Natural Product Drug Discovery Through Systematic Sampling of Diverse Texas Soils

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2020

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Cheng, Eric
Currens, Grant
Patel, Rinkal

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Abstract

Purpose: To prove a concept of discovering microbial natural products through systematic sampling of diverse Texas soils by constructing and screening a pilot library of secondary metabolites produced by Texas soil-derived microbes for cytotoxicity against three human cancer cell lines. Methods: Secondary metabolites were extracted from microbial isolates using MeOH and EtOAc. These metabolites were fractionated by flash chromatography and screened for cytotoxicity against MIA PaCa-2, SH-SY5Y, and COLO 829 using an ATP-luciferase assay. A short-list of active fractions was compiled and further activity-guided purification through HPLC was performed to purify the active compounds. From this, isolated active compounds were identified through methods including TOF-MS, MS/MS, NMR, and X-ray crystallography. Results: Malformin, a bicyclic pentapeptide which has been shown to elicit potent anti-cancer effects was purified and helped to validate our methodology. Subsequently, two related compounds, Aspergillin PZ and Trichoderone B, exhibiting anti-cancer effects were purified from a fungal isolate. Though previously identified, these compounds have not been extensively studied for their general cytotoxicity or differential potency, and have thus been enrolled in the US National Cancer Institute - 60 human tumor cell lines screen (NCI60). Conclusions: While a previously unidentified compound has not yet been discovered through this pilot study, bioactive secondary metabolites have been re-discovered which not only validates our methodology but also provides promising opportunity to address gaps in scientific understanding of previously reported compounds. Theoretically, enlarging our library size should afford new and active natural products.

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