The Identification and Heterologous Expression of the Biosynthetic Gene Cluster Encoding the Antibiotic and Anticancer Agent Marinomycin.

With the rise in antimicrobial resistance, there is an urgent need for new classes of antibiotic with which to treat infectious disease. Marinomycin, a polyene antibiotic from a marine microbe, has been shown capable of killing methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF), as well as having promising activity against melanoma. An attractive solution to the photoprotection of this antibiotic has been demonstrated. Here, we report the identification and analysis of the marinomycin biosynthetic gene cluster (BGC), and the biosynthetic assembly of the macrolide. The marinomycin BGC presents a challenge in heterologous expression due to its large size and high GC content, rendering the cluster prone to rearrangement. We demonstrate the transformation of Streptomyces lividans using a construct containing the cluster, and the heterologous expression of the encoded biosynthetic machinery and production of marinomycin B.

A natural solution to photoprotection and isolation of the potent polyene antibiotic, marinomycin A.

The photoprotection and isolation of marinomycin A using sporopollenin exine capsules (SpECs) derived from the spores of the plant Lycopodium clavatum is described. The marinomycins have a particularly short half-life in natural light, which severely impacts their potential biological utility given that they display potent antibiotic and anticancer activity. The SpEC encapsulation of the marinomycin A dramatically increases the half-life of the polyene macrodiolide to the direct exposure to UV radiation by several orders of magnitude, thereby making this a potentially useful strategy for other light sensitive bioactive agents. In addition, we report that the SpECs can also be used to selectively extract culture broths that contain the marinomycins, which provides a significantly higher recovery than with conventional XAD resins and provides concomitant photoprotection.

Bluegenics: Bioactive Natural Products of Medicinal Relevance and Approaches to Their Diversification.

Nature provides a valuable resource of medicinally relevant compounds, with many antimicrobial and antitumor agents entering clinical trials being derived from natural products. The generation of analogues of these bioactive natural products is important in order to gain a greater understanding of structure activity relationships; probing the mechanism of action, as well as to optimise the natural product's bioactivity and bioavailability. This chapter critically examines different approaches to generating natural products and their analogues, exploring the way in which synthetic and biosynthetic approaches may be blended together to enable expeditious access to new designer natural products.