These environments cover >70% of the earth’s surface, and contain 95% of the biosphere, including millions of phylogenetically divergent microorganisms, thus offering an as yet largely untapped treasure of chemical biodiversity. This scenario has encouraged scientists to explore less accessible and until now less investigated environments and ecosystems such as those found in the oceans, and in fact marine natural products are assuming an increasingly central role in the search for novel bioactivities. Recent analyses have however underlined that appreciable numbers of NPs with novel chemical features or scaffolds are still being discovered every year, even though the frequency of such findings has been decreasing over time. Although on average ~1000 new NPs have been discovered each year over the last two decades, the recurrent rediscovery of already known compounds continues to be a major bottleneck in the field. In particular, antimicrobial resistance (AMR) has been recognized as one of the main threats to humanity, with the frightening prediction of ~10 million deaths due to AMR by 2050, if immediate action is not taken. Such phenomena have become some of the most pressing issues in modern society. However, by their very nature pathogenic microbes and cancer cells are evolving entities, which are increasingly developing resistance mechanisms against the latest generation of medical treatments. Microbial NPs have proven useful in the treatment of viral, fungal, and bacterial infections, as well as in the treatment of various cancers. More than 10% of bioactive NPs are microbial in origin, and in the last decades, microorganisms have assumed a central role in the reinvigorated field of NP discovery. The majority of medically relevant NPs are secondary metabolites (SMs), which are generally and historically defined as molecules not essential for the survival of the producing organism but which aid in increasing its competitiveness. Between 50% and 70% of today’s small molecule-based therapeutics have originated from NPs, underlying the pivotal role these compounds play in modern medicine. Natural products (NPs) are organic molecules produced by living organisms, and in the last century, their applications have underpinned fundamental advances in both the industrial and medical fields. We believe that natural products discovery in marine microorganisms would be greatly aided through the integration of basic microbiological approaches, computational methods, and technological innovations, thereby helping unearth much of the as yet untapped potential of these microorganisms. Nevertheless, we believe that some computation and experimental based techniques which are used in other disciplines, and which we discuss could be effectively employed to help streamline the OSMAC based approaches. Unfortunately, the empirical nature of the OSMAC approach forces scientists to perform extensive laboratory experiments. Moreover, we underline how changes in some parameters which have provided important results in terrestrial microbes, but which have rarely been considered in marine microorganisms, may represent additional strategies to awaken “silent” gene clusters in marine microbes. In this review, we aim to provide a focused and comprehensive overview of these strategies as they pertain to marine microbes. As a direct extension of such approaches, co-cultivation strategies and the addition of chemical elicitors have also been used as cues to activate “silent” clusters. Parameters such as, nutrient content, temperature, and rate of aeration can be easily changed, altering the global physiology of a microbial strain and in turn significantly affecting its secondary metabolism. The principles behind the cultivation based approaches have been conceptualized in the “one strain many compounds” (OSMAC) framework, which underlines how a single strain can produce different molecules when grown under different environmental conditions. Therefore, both genetic and cultivation-based techniques have been developed aimed at stimulating expression of these “silent” genes. Triggering expression of these “silent” clusters could result in unlocking the chemical diversity they control, allowing the discovery of novel molecules of both medical and biotechnological interest. Such gene clusters are generally considered as “silent”, meaning that they are not expressed under laboratory conditions.

Genomic data often highlights an inconsistency between the number of gene clusters identified using bioinformatic approaches as potentially producing secondary metabolites and the actual number of chemically characterized secondary metabolites produced by any given microorganism.

Andy osmac