## 1 Introduction  
The realization that microorganisms produce a vast array of diverse and functionally attractive compounds has underpinned medical and industrial developments over the decades. As recent as 2012, for small-molecule pharmaceuticals, 68% of the anticancer agents and 52% of the anti-infective agents are natural products, or derived from natural products [1]. Indeed, natural products are known to reflect the diversity and richness of our natural ecosystems, honed through infinite stages of evolutionary development. The diversity of producing organisms is probably still underestimated, with current bioactive microbial products, _i.e._, antifungal, antibacterial, antiviral, cytotoxic and immunosuppressive agents, being isolated primarily from the fungal kingdom (_ca._ 42%), followed by strains belonging to the genus _Streptomyces_ (32.1%) [2; 3]. The culturable bottleneck that exists with the isolation and cultivation of marine isolates supports the expectation of a currently untapped reservoir of producing organisms. However, this diversity brings with it its own challenges whereby partly understood living organisms replace defined synthetic systems as the source of these potential drug products. While chemical synthesis programmes, challenging as they are, provide stepwise closed system production pipelines, isolation and production of secondary metabolites from living organisms requires detailed understanding of the physiology of the producing species, something that may not be readily available for newly isolated marine bacteria. The biosynthetic capacity for small molecule production more often than not resides within discrete localized sections of the microbial genome, hence the term \"biosynthetic gene clusters\" (BGCs). Different classes exist, categorized based on the type of small molecular entity produced, with nonribosomal peptide synthetases (NRPSs), polyketides (PKs), ribosomally synthesized and post-translationally modified peptides (RiPPs), terpenoids, saccharides, and hybrid compounds being the most widely characterized. Typically exhibiting a characteristic modularity of enzymatic domains, BGCs can exceed 100 kb in size, a feature that creates significant bottlenecks in the use of molecular biology approaches to capture their activities [4]. Evolutionary insights into how nature can evolve new natural products have provided a basis upon which to interpret the diversity of existing BGCs [5]. While the diversity of chemical structures produced by BGCs is as vast as the biological activities they exhibit, the core enzymology used to biosynthesize these natural products is conserved. Many BGCs consist of repeating units or modules typically controlling the incorporation of one molecular entity into the final structure. As a result, the structural diversity of, e.g., the NRPS-synthesized natural products comes from variations in the number and order of the modules or amino acids incorporated [6]. Notwithstanding this, early predictions of a mix and match natural combinatorial strategy have not yet been realized, with active clusters exhibiting an exquisite level of conserved functionality. The traditional approach used for the bioassay-guided discovery of secondary metabolites, or natural products, has been based on the cultivation of microorganisms, chemical extraction of the produced metabolites, and final structure elucidation. Although this work-flow allowed the discovery of many valuable chemicals, nowadays it leads too often to rediscovery of known metabolites, leading to a dramatic reduction in the number of new molecules described [7]. A consequence of this is the declining number of new chemical entities (NCEs) in the drug development pipeline that have been observed in recent years (Figure 1), recently reviewed by both Gaudencio & Pereira and [PERSON] and colleagues [8,9].