Abstract
Natural products (NP) are a valuable drug resource. However, NP-inspired drug leads are declining, among other reasons due to high re-discovery rates. We developed a conceptual framework using the metabolic fingerprint of entire ecosystems (MeE) to facilitate the discovery of global bioactivity hotspots. We assessed the MeE of 305 sites of diverse aquatic ecosystems, worldwide. All samples were tested for antiviral effects against the human immunodeficiency virus (HIV), followed by a comprehensive screening for cell-modulatory activity by High-Content Screening (HCS). We discovered a very strong HIV-1 inhibition mainly in samples taken from fjords with a strong terrestrial input. Multivariate data integration demonstrated an association of a set of polyphenols with specific biological alterations (endoplasmic reticulum, lysosomes, and NFkB) caused by these samples. Moreover, we found strong HIV-1 inhibition in one unrelated oceanic sample closely matching to HIV-1-inhibitory drugs on a cytological and a chemical level. Taken together, we demonstrate that even without physical purification, a sophisticated strategy of differential filtering, correlation analysis, and multivariate statistics can be employed to guide chemical analysis, to improve de-replication, and to identify ecosystems with promising characteristics as sources for NP discovery.
Highlights
Natural products (NP) are a valuable drug resource
We applied non-targeted Ultra-high resolution (UHR) mass spectrometry to capture the chemical space of 305 metabolic fingerprint of entire ecosystems (MeE) samples collected in five continents (Europe, Africa, Australia, North America and Antarctica) at different sites in aquatic ecosystems (Fig. 1a)
The organic material contained in the water samples was concentrated by solid phase extraction (SPE) prior to analysis (Fig. S1b)
Summary
Natural products (NP) are a valuable drug resource. NP-inspired drug leads are declining, among other reasons due to high re-discovery rates. Imaging-based High-Content Screening (HCS) using a set of fluorescence dyes or antibodies that target several cellular structures has recently emerged as a promising tool for more holistic screenings[14,15,16,17,18,19] It provides a powerful strategy for non-targeted (unbiased) biological profiling of alterations caused by small molecules and for prediction of compound-related mode of action (MoA)[14,15]. To our best knowledge only Kurita et al.[20] and Kremb et al.[21] initiated this type of analysis, but with samples of low complexity and using only a limited set of cellular structures Another strategy for the identification of NP candidates with promise is the screening for antiviral activities, such as inhibition of the human immunodeficiency virus type-1 (HIV-1). This has been successfully demonstrated for a broad variety of complex mixtures of natural products, using a robust phenotypic screening assay encompassing the entire HIV replication cycle (EASY-HIT)[22,23,24,25,26]
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