Abstract
Unlocking the rich harvest of marine microbial ecosystems has the potential to both safeguard the existence of our species for the future, while also presenting significant lifestyle benefits for commercial gain. However, while significant advances have been made in the field of marine biodiscovery, leading to the introduction of new classes of therapeutics for clinical medicine, cosmetics and industrial products, much of what this natural ecosystem has to offer is locked in, and essentially hidden from our screening methods. Releasing this silent potential represents a significant technological challenge, the key to which is a comprehensive understanding of what controls these systems. Heterologous expression systems have been successful in awakening a number of these cryptic marine biosynthetic gene clusters (BGCs). However, this approach is limited by the typically large size of the encoding sequences. More recently, focus has shifted to the regulatory proteins associated with each BGC, many of which are signal responsive raising the possibility of exogenous activation. Abundant among these are the LysR-type family of transcriptional regulators, which are known to control production of microbial aromatic systems. Although the environmental signals that activate these regulatory systems remain unknown, it offers the exciting possibility of evoking mimic molecules and synthetic expression systems to drive production of potentially novel natural products in microorganisms. Success in this field has the potential to provide a quantum leap forward in medical and industrial bio-product development. To achieve these new endpoints, it is clear that the integrated efforts of bioinformaticians and natural product chemists will be required as we strive to uncover new and potentially unique structures from silent or cryptic marine gene clusters.
Highlights
The realization that microorganisms produce a vast array of diverse and functionally attractive compounds has underpinned medical and industrial developments over the decades
While the identification of silent gene clusters has already expanded our consideration of the biosynthetic ability of microorganisms, the development of multiple approaches to stimulate the production of unknown secondary metabolites remains a key challenge in harnessing the value of these cryptic systems (Figure 2)
When we consider that these regions typically exist in a heterochromatin state, where gene expression requires epigenetic control, a role in the expression of silent gene clusters linked to natural product expression appeared likely
Summary
The realization that microorganisms produce a vast array of diverse and functionally attractive compounds has underpinned medical and industrial developments over the decades. The culturable bottleneck that exists with the isolation and cultivation of marine isolates supports the expectation of a currently untapped reservoir of producing organisms 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. Even with the best advances in culturing 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]. While the identification of silent gene clusters has already expanded our consideration of the biosynthetic ability of microorganisms, the development of multiple approaches to stimulate the production of unknown secondary metabolites remains a key challenge in harnessing the value of these cryptic systems (Figure 2). This review aims to present an overview on the most successful approaches adopted so far, focusing on the unexplored potential hidden in marine microorganisms
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