## 1 Introduction
Having already identified \(>\)2000 antibiotics after screening of \(\geq\)10 million microbes, there is a clear realization that, following traditional approaches, the antibiotics yet to be discovered are likely to be produced by microbes less abundant than those that have already been discovered [10]. If this is true, and taking actinomycetes as an example, that means that new antibiotic producing actinomycetes will be picked at frequencies \(\leq\)10\({}^{-7}\) per random isolate. Finding the precious few will require the screening of tens of millions of actinomycetes, while excluding or rapidly deregulating the known antibiotics [10]. To counteract the pending stasis in novel product discovery, new approaches are needed to unlock the full potential of the \"microgenome\". A key driver of this will be unlocking the silent potential of the microbial world, activating those systems that heretofore have remained locked away within the complex communities in which they are naturally produced. In some cases, simply culturing a new organism will unlock novel bioactive compounds as seen with the isolation of the arugosins from the marine-derived fungus _Emericella nidulans_ var. _acristata_ or deoxypolophyllotoxin, a pro-drug of the anticancer drug podophyllotoxin, in the endophytic fungus _Aspergillus fumigatus_ Fresenius [11,12]. However, even with the best advances in culturing  
Figure 1: The decline in new chemical entities (NCE) development has continued in spite of an exponential increase in biosynthetic gene clusters (BGC) discovery. There has been more than a 50% reduction in the number of NCEs being approved by the FDA which can be categorized as natural products or derived from such. This has occurred at the same time that an explosion of papers citing “biosynthetic gene clusters” has emerged in the literature. Notwithstanding the lag time in drug development, serious bottlenecks exist in translating the bioactive potential from these microbial systems. technologies, there remains a significant untapped resource within microbial genomes, as evidenced by the advent of high throughput sequencing technology. These data revealed that the biosynthetic abilities of even the most well characterized organisms has been greatly unexplored [13,14]. In fact, the number of biosynthetic genes in many bacteria and fungi greatly outnumbers the known metabolites described for these organisms. This has led to the term \"silent\" or \"cryptic\" genes being phrased. For example, the model fungus _A. nidulans_ is potentially able to produce 32 polyketides, 14 non-ribosomal peptides and two indole alkaloids [15,16], with little more than 50% of the produced secondary metabolites being yet identified. There are several reasons for such an observation. In the first place it could be that, under laboratory cultivation conditions, the metabolites are produced in such an amount that cannot be easily detected. On the other hand, it is possible that the biosynthetic genes are not expressed, because their activation relies on environmental cues missing in laboratory conditions. Even if weakly expressed, the presence of toxic or PAIN (pan-assay interference) compounds may mask the effects of the low abundance compounds in question, making them more difficult to detect in the sea of secondary metabolites, while high throughput technologies have thus far failed to keep pace with the requirements of drug development pipelines. Furthermore, while much focus has centered on the production of specific compounds from defined pathway, it has also become clear that many compounds can emerge from a single pathway, depending on the culture conditions and the mechanisms used to elicit activation [17,18]. In some ways, the silence of marine BGCs is analogous to the deafening quiet on standard culture media plates when marine samples are harvested. Our inability to cultivate the marine microflora, and particularly the low abundant producers of potentially novel natural products, feeds into the bottleneck in the pipeline of natural product discovery.