Advanced identification of global bioactivity hotspots via screening of the metabolic fingerprint of entire ecosystems

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.

Antioxidant Activity and Phenolic Content of Marine Dissolved Organic Matter and Their Relation to Molecular Composition

“…Chemometric methodology was established because of the need to analyze highly complex databases generated from non-targeted approaches such as transcriptomics, proteomics or metabolomics (Trygg et al, 2006). This approach could be extrapolated to different bioactivities within the pharmaceuticals and cosmeceuticals, as already employed by Zhernov et al (2017); Tuttle et al (2019), or Mueller et al (2020. All these studies, including ours, have in common the merging and success of non-targeted chemical characterization with pharmaceutical or cosmeceutical analyses.…”

“…The combination presented in this study, consisting of merging non-targeted chemical characterization with pharmaceutical or cosmeceutical analyses to identify different modes of bioactivity in organic complex mixtures, is arising. Following this approach, Mueller et al (2020), in their proofof-concept study, illustrated that DOM collected from different sites in aquatic ecosystems (marine, terrestrial, perturbed by humans) harbor distinct antiviral activities. Zhernov et al (2017) suggested anti-HIV activities inherent to diverse natural humic supramolecular assemblies from silt sulfide mud with medicinal properties.…”

Marine dissolved organic matter: a vast and unexplored molecular space

“…Recently, a multiplexed screening strategy combined analysis using cytological profiling and metabolomics yielding bioactivity characterization termed “metabolic fingerprints of entire ecosystems” (Müller et al 2020 ). First, untargeted ultrahigh-resolution mass spectrometry was used to capture the chemical space of 305 aquatic ecosystem samples collected across five continents (Europe, Africa, Australia, North America, and Antarctica).…”

“…With the recent and general resurgent interest in natural extracts, bioactivities detected by empirical screening analyses, may not necessarily require chemical isolation in order to be legally subject to regulatory standardization. Distinct biological activities detected in samples collected from diverse ecosystems is burgeoning interest in DOM for a variety of biotechnological, pharmaceutical, and “cosmeceutical” applications (Catalá et al 2020 ; Müller et al 2020 ; Zhernov et al 2016 ). Innovative combined technologies screening for bioactivities using untargeted biological models and chemical analysis are certainly helping dive deeper into characterization of the biotechnological potential of marine DOM.…”

“…In this context, marine dissolved organic matter (DOM) represents a new paradigm shift in the blue biotechnological field. Marine DOM consists a large degree of small organic acids with amphiphilic properties that can be extracted from seawater through adsorption onto hydrophobic resins and promises a yet unexploited potential for blue biotechnology (Catalá et al 2020 ; Müller et al 2020 ). However, studying the biotechnological potential of DOM requires a variety of technical challenges to be addressed, and chemometric analytical fractionation is necessary to identify and isolate specific bioactivities therein.…”