Abstract
The marine environment is an excellent resource for natural products with therapeutic potential. Its microbial inhabitants, often associated with other marine organisms, are specialized in the synthesis of bioactive secondary metabolites. Similar to their terrestrial counterparts, marine Actinobacteria are a prevalent source of these natural products. Here, we discuss 77 newly discovered alkaloids produced by such marine Actinobacteria between 2017 and mid-2021, as well as the strategies employed in their elucidation. While 12 different classes of alkaloids were unraveled, indoles, diketopiperazines, glutarimides, indolizidines, and pyrroles were most dominant. Discoveries were mainly based on experimental approaches where microbial extracts were analyzed in relation to novel compounds. Although such experimental procedures have proven useful in the past, the methodologies need adaptations to limit the chance of compound rediscovery. On the other hand, genome mining provides a different angle for natural product discovery. While the technology is still relatively young compared to experimental screening, significant improvement has been made in recent years. Together with synthetic biology tools, both genome mining and extract screening provide excellent opportunities for continued drug discovery from marine Actinobacteria.
Highlights
Natural products, small molecules isolated from biological sources, have long been recognized for their huge potential in human medicine and are still gaining traction in recent years
The quinoline core was synthesized by a sesterterpene diphosphate synthase, a prenyltransferase, two β-ketoacyl-acyl carrier protein (ACP) synthases, an ACP, Dtriaegnos,feCraalsifeorcnoiar.eIennstzeyadmoefwteestriengprfoorpaonsteimd ifcororbsiualbascetqivuiteienst odrecryivtoattoixziacteioffn elucidation of the marinoterpin biosynthetic gene cluster was the main objectiv on the biosynthetic knowledge of aurachins A-D, compounds that show similari 72, a proposal was made
Though progress is being made on genome mining for novel alkaloids, often relying on the identification of NRPS and polyketide synthases (PKSs) clusters, biosynthesis pathways are frequently puzzling or obscured, resulting in few hypothetical biochemical synthesis routes being proposed by authors
Summary
Small molecules isolated from biological sources, have long been recognized for their huge potential in human medicine and are still gaining traction in recent years. Combined with varied conditions of temperature, pressure, acidity, and light, the marine environment is a true cauldron for novel natural product discovery [3], including compounds with naturally rare atoms. Despite such versatile environmental conditions yielding a plethora of unique secondary metabolites and the up to four times higher success rate in drug discovery, marine natural products are still underrepresented [4]. While numerous reviews about marine Actinobacteria and their secondary metabolites address the compounds in general (e.g., halogenated molecules [9]) or revise their biological functionalities (e.g., biofilm inhibition [10]), an overview of recently discovered alkaloids produced by marine Actinobacteria is missing. We discuss the power of synthetic biology to bridge the gap between compound discovery and production
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