Teresa S. Catalá, Spencer Shorte & Thorsten Dittmar
Applied Microbiology and Biotechnology volume 105, pages 7225–7239 (2021)
Welcome to your blog post. Use this space to connect with your readers and potential customers in a way that’s current and interesting. Think of it as an ongoing conversation where you can share updates about business, trends, news, and more.
Abstract
Marine dissolved organic matter (DOM) comprises a vast and unexplored molecular space. Most of it resided in the oceans for thousands of years. It is among the most diverse molecular mixtures known, consisting of millions of individual compounds.
More than 1 Eg of this material exists on the planet. As such, it comprises a formidable source of natural products promising significant potential for new biotechnological purposes. Great emphasis has been placed on understanding the role of DOM in biogeochemical cycles and climate attenuation, its lifespan, interaction with microorganisms, as well as its molecular composition. Yet, probing DOM bioactivities is in its infancy, largely because it is technically challenging due to the chemical complexity of the material. It is of considerable interest to develop technologies capable to better discern DOM bioactivities.
Modern screening technologies are opening new avenues allowing accelerated identification of bioactivities for small molecules from natural products. These methods diminish a priori the need for laborious chemical fractionation. We examine here the application of untargeted metabolomics and multiplexed high-throughput molecular-phenotypic screening techniques that are providing first insights on previously undetectable DOM bioactivities.
Key points
• Marine DOM is a vast, unexplored biotechnological resource.
• Untargeted bioscreening approaches are emerging for natural product screening.
• Perspectives for developing bioscreening platforms for marine DOM are discussed.
Introduction
Natural products (NPs) from plants have been used in various branches of traditional medicine for millennia (Chassagne et al. 2019) and, according to the World Health Organization (WHO), comprise primary health care therapy for ca. 80% of the population in developing countries (Farnsworth et al. 1985). Accordingly, for three decades, pharmaceutical companies have turned drug discovery efforts toward screening chemical libraries containing pure active compounds isolated from “medicinal” plants (Strebhardt and Ullrich 2008).
As such the single “magic bullet” paradigm has dominated in the form of industrialized target-based drug-discovery screening campaigns trawling through ever larger chemical libraries (i.e., > 2 M compounds). However, such efforts have suffered high attrition rates, yielding limited success toward discovery of new first-in-class drugs (Chassagne et al. 2019). In this scenario, searching the potential of NPs is made difficult by technical constraints, for example the need to detect biological activities and isolate the active compounds responsible. Accordingly, novel screening strategies are actively sought (Horvath et al. 2016).
In comparison with chemical scaffolds from known drugs, NPs span a wider and different chemical space than synthetic derivatives (Feher and Schmidt 2002; Ganesan 2008; Grabowski and Schneider 2007), and still fewer than 20% of NP core structures and scaffolds are represented in commercial compound libraries (Hert et al. 2009). In this sense, NP chemical diversity, structural complexity, and their biological selectivity present both an opportunity and a technical challenge for the development of novel drugs (Atanasov et al. 2015; Clardy and Walsh 2004).
It is striking that while most NPs come from plants, many of today’s most useful medicines come from bacterial sources (Bérdy 2005). Most bacterial metabolites are laboratory isolated, with only a small subset being understood at the level of the biological chemistry underlying their natural production (Davies 2006; Ueda 2021). Understanding how microbe interactions and micro-environment influence metabolite production and NP biosynthesis is an active area of research (Burgess et al. 1999; Patin et al. 2018; Traxler et al. 2013; Trischman et al. 2004), especially in the context of marine sediments (Tuttle et al. 2019). This is because marine NPs harbor the largest part of our planet’s natural biodiversity (Mora et al. 2011) and has resulted in a long tradition of searching for new bioactive compounds from marine sources (Blunt et al. 2014; Gerwick and Moore 2012).
Marine NPs are extracted from marine organisms, such as bacteria (Baran et al. 2011; Mansson et al. 2011; Shin et al. 2010; Wienhausen et al. 2017; Wietz et al. 2010), microalgae or macroalgae (La Barre et al. 2010; Parrot et al. 2019; Payo et al. 2011), fungi (Capon et al. 2003; Elnaggar et al. 2016; Höller et al. 2000; Kim et al. 2016; Klemke et al. 2004; Lang et al. 2007; Li et al. 2010; Luo et al. 2004), or animals (Alvarez et al. 2010; Connor and Gracey 2012; Ivanešivic et al. 2011; Karakash et al. 2009; Sarma et al. 2009; Schock et al. 2010; Soanes et al. 2011; Utermann et al. 2018). In recent years, the search for new marine NPs has strongly shifted from macroorganisms to microorganisms, whereby 57% of new marine NPs reported came from marine microbial sources (Carroll et al. 2019). 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.
Abstract
Marine dissolved organic matter (DOM) comprises a vast and unexplored molecular space. Most of it resided in the oceans for thousands of years. It is among the most diverse molecular mixtures known, consisting of millions of individual compounds.
More than 1 Eg of this material exists on the planet. As such, it comprises a formidable source of natural products promising significant potential for new biotechnological purposes. Great emphasis has been placed on understanding the role of DOM in biogeochemical cycles and climate attenuation, its lifespan, interaction with microorganisms, as well as its molecular composition. Yet, probing DOM bioactivities is in its infancy, largely because it is technically challenging due to the chemical complexity of the material. It is of considerable interest to develop technologies capable to better discern DOM bioactivities.
Modern screening technologies are opening new avenues allowing accelerated identification of bioactivities for small molecules from natural products. These methods diminish a priori the need for laborious chemical fractionation. We examine here the application of untargeted metabolomics and multiplexed high-throughput molecular-phenotypic screening techniques that are providing first insights on previously undetectable DOM bioactivities.
Key points
• Marine DOM is a vast, unexplored biotechnological resource.
• Untargeted bioscreening approaches are emerging for natural product screening.
• Perspectives for developing bioscreening platforms for marine DOM are discussed.
Introduction
Natural products (NPs) from plants have been used in various branches of traditional medicine for millennia (Chassagne et al. 2019) and, according to the World Health Organization (WHO), comprise primary health care therapy for ca. 80% of the population in developing countries (Farnsworth et al. 1985). Accordingly, for three decades, pharmaceutical companies have turned drug discovery efforts toward screening chemical libraries containing pure active compounds isolated from “medicinal” plants (Strebhardt and Ullrich 2008).
As such the single “magic bullet” paradigm has dominated in the form of industrialized target-based drug-discovery screening campaigns trawling through ever larger chemical libraries (i.e., > 2 M compounds). However, such efforts have suffered high attrition rates, yielding limited success toward discovery of new first-in-class drugs (Chassagne et al. 2019). In this scenario, searching the potential of NPs is made difficult by technical constraints, for example the need to detect biological activities and isolate the active compounds responsible. Accordingly, novel screening strategies are actively sought (Horvath et al. 2016).
In comparison with chemical scaffolds from known drugs, NPs span a wider and different chemical space than synthetic derivatives (Feher and Schmidt 2002; Ganesan 2008; Grabowski and Schneider 2007), and still fewer than 20% of NP core structures and scaffolds are represented in commercial compound libraries (Hert et al. 2009). In this sense, NP chemical diversity, structural complexity, and their biological selectivity present both an opportunity and a technical challenge for the development of novel drugs (Atanasov et al. 2015; Clardy and Walsh 2004).
It is striking that while most NPs come from plants, many of today’s most useful medicines come from bacterial sources (Bérdy 2005). Most bacterial metabolites are laboratory isolated, with only a small subset being understood at the level of the biological chemistry underlying their natural production (Davies 2006; Ueda 2021). Understanding how microbe interactions and micro-environment influence metabolite production and NP biosynthesis is an active area of research (Burgess et al. 1999; Patin et al. 2018; Traxler et al. 2013; Trischman et al. 2004), especially in the context of marine sediments (Tuttle et al. 2019). This is because marine NPs harbor the largest part of our planet’s natural biodiversity (Mora et al. 2011) and has resulted in a long tradition of searching for new bioactive compounds from marine sources (Blunt et al. 2014; Gerwick and Moore 2012).
Marine NPs are extracted from marine organisms, such as bacteria (Baran et al. 2011; Mansson et al. 2011; Shin et al. 2010; Wienhausen et al. 2017; Wietz et al. 2010), microalgae or macroalgae (La Barre et al. 2010; Parrot et al. 2019; Payo et al. 2011), fungi (Capon et al. 2003; Elnaggar et al. 2016; Höller et al. 2000; Kim et al. 2016; Klemke et al. 2004; Lang et al. 2007; Li et al. 2010; Luo et al. 2004), or animals (Alvarez et al. 2010; Connor and Gracey 2012; Ivanešivic et al. 2011; Karakash et al. 2009; Sarma et al. 2009; Schock et al. 2010; Soanes et al. 2011; Utermann et al. 2018). In recent years, the search for new marine NPs has strongly shifted from macroorganisms to microorganisms, whereby 57% of new marine NPs reported came from marine microbial sources (Carroll et al. 2019). 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.
Marine DOM: a plethora of chemicals
Marine DOM is one of the largest reservoirs of reduced organic carbon on the planet’s surface. The average liter of seawater contains < 1 mg of DOM, but considering the vast volume of the oceans, this adds up to a global reservoir exceeding 1 Eg of DOM (662 ± 32 Pg carbon; Hansell et al. 2009). As such, DOM contains a similar amount of carbon as atmospheric CO2 (860 Pg carbon; Friedlingstein et al. 2019) and holds > 200 times the carbon inventory of the total marine biomass (Hansell et al. 2009).
DOM is continuously released by all organisms in the ocean while they live and upon death. In addition, water-soluble decomposition products from vascular plants are carried by rivers into the ocean. Most DOM quickly turns over by marine microorganisms, but a minor fraction turns over very slowly and has accumulated over several millennia to the observable pool of DOM. Marine DOM contains millions of different compounds of low molecular mass and, therefore, is unarguably one of the most complex chemical mixtures on Earth (Dittmar 2015), comprising extremely low concentrations of diverse chemical constituents (Arrieta et al. 2015; Zark et al. 2017).
Many of the DOM compounds are alicyclic, organic acids with amphiphilic properties (Dittmar and Kattner 2003; Hertkorn et al. 2006; Zark et al. 2017), and are similar in structure regardless of the aquatic origin (Zark and Dittmar 2018). While these general structural features are known, the full structure of only a very minor fraction of the compounds residing in DOM is known (Dittmar and Stubbins 2014) (Fig. 1).