Marine Microorganism-Invertebrate Assemblages: Perspectives to Solve the “Supply Problem” in the Initial Steps of Drug Discovery

Abstract

The chemical diversity associated with marine natural products (MNP) is unanimously acknowledged as the “blue gold” in the urgent quest for new drugs. Consequently, a significant increase in the discovery of MNP published in the literature has been observed in the past decades, particularly from marine invertebrates. However, it remains unclear whether target metabolites originate from the marine invertebrates themselves or from their microbial symbionts. This issue underlines critical challenges associated with the lack of biomass required to supply the early stages of the drug discovery pipeline. The present review discusses potential solutions for such challenges, with particular emphasis on innovative approaches to culture invertebrate holobionts (microorganism-invertebrate assemblages) through in toto aquaculture, together with methods for the discovery and initial production of bioactive compounds from these microbial symbionts.

Bacterial communities from corals cultured ex situ remain stable under different light regimes — Relevance for in toto aquaculture

“…The ANOSIM further confirmed that coral fragmentation did not significantly affect (R = 0.302; P = 0.086) the structure of the bacterial community recorded in the mother colonies and coral fragments stocked under the same PAR intensity (120 μmol quanta m −2 s −1 ). These results are relevant to support in toto aquaculture (the culture of the holobiont-cnidarian host and associated microorganisms) as a tool to supply microbial biomass associated with marine invertebrates, namely corals, for drug discovery (Leal et al, 2013(Leal et al, , 2014. Indeed, if no significant shifts occur in the structure of the bacterial community present in coral fragments, in toto aquaculture may contribute to solve the "supply problem" (see Leal et al, 2014), as microorganisms producing target metabolites in mother colonies are more likely to have been retained during fragmentation and/or growout.…”

“…These results are relevant to support in toto aquaculture (the culture of the holobiont-cnidarian host and associated microorganisms) as a tool to supply microbial biomass associated with marine invertebrates, namely corals, for drug discovery (Leal et al, 2013(Leal et al, , 2014. Indeed, if no significant shifts occur in the structure of the bacterial community present in coral fragments, in toto aquaculture may contribute to solve the "supply problem" (see Leal et al, 2014), as microorganisms producing target metabolites in mother colonies are more likely to have been retained during fragmentation and/or growout. Well established protocols for the propagation ex situ of Sarcophyton are already available (Calfo, 2007;Sella and Benayahu, 2010), which allow the production of coral biomass using simple and economically feasible zootechnical procedures.…”

“…This finding supports the suitability of this coral species for in toto aquaculture. Future studies addressing the supply issue of target microorganisms associating with other coral species (as suggested by Leal et al, 2013Leal et al, , 2014 should survey potential shifts in their microbial communities during initial culture trials. While PCR-DGGE may present a number of pitfalls when addressing band identification (for a detailed discussion on these issues please see Sekiguchi et al, 2001;Kušar and Avguštin, 2012;Neilson et al, 2013), researchers may still rely on the use of this rather inexpensive molecular approach to monitor significant shifts in microbial community structure (Neilson et al, 2013) among a priori defined groups (Cleary et al, 2012).…”

Symbiotic Microbes from Marine Invertebrates: Driving a New Era of Natural Product Drug Discovery

“…In fact it is estimated that as many as 99% are considered "unculturable" [107], thus making the screening and mass-production of any pharmaceuticals they produce very difficult using common culturing methods [85]. One seemingly simple solution to this problem is to culture the host organism along with the symbiont, in a manner that maximises secondary metabolite production by the microbe [21, 108,109]. However, this adds an extra level of complexity to the culturing procedure, having to accommodate the needs of an entire complex holobiont.…”

Modelling sponge-symbiont metabolism

“…For instance, marine sponges are valued for their ecosystem services, in particular cycling and retaining nutrients on coral reefs (Alexander et al, 2014;de Goeij et al, 2013;Rix et al, 2016), and as a source of bioactive secondary metabolites with commercial potential (Blunt et al, 2014;Konstantinidis & Tiedje, 2004;Leal et al, 2012;Mehbub et al, 2014;Thomas et al, 2010). It is accepted that the low commercialisation rate of sponge holobiont derived natural products is due to the inability to reliably produce sponge biomass (Belarbi, 2003;Leal et al, 2014;Osinga et al, 1999;Schippers et al, 2012;Sipkema et al, 2005;Wijffels, 2008). Simplified, growth is the catabolic and anabolic conversion of food by the central metabolic network into biomass.…”