Chemical and Genetic Triggers of Secondary Metabolite Production

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For over fifty years natural products were the primary source of new drug leads, in many cases moving from isolation to clinic use without modification. Most of these compounds were isolated from bacteria and fungi, the product of a massive industrial effort to isolate cultivable strains from every corner of the globe. This search largely ended two decades ago, due in part to diminishing returns from continual re-isolation of known compounds. The absence of new natural products has hit anticancer and antibiotic research the hardest, as approximately 40% and 80% of small molecule antibiotics and anticancer drugs are natural product based. Recent advances in bioinformatics allow us to identify the genes and proteins involved in natural product biosynthesis, without needing to isolate each compound. These tools reveal that earlier searches for natural products have missed the vast majority of compounds, with even the most productive strains producing only about 20% of their biosynthetic repertoire during normal lab growth. Interestingly, the regulatory elements that control these silent genes appear to be heavily conserved, suggesting that the majority of silent biosynthesis genes rely on a small set of chemical triggers. With bacteria from the related Photorhabdus and Xenorhabdus families as a model, we will use high throughput screening to discover natural products that activate natural product biosynthesis. In concert with genetic studies these activators will provide a handle by which we can probe the regulatory pathways that control secondary metabolism in bacteria. Linking natural product biosynthesis to specific chemical triggers will also make it possible to tie the secondary metabolites bacteria produce to specific environmental stresses, shedding light on how these compounds allow bacteria to adapt to their environment. The chemical triggers will also be a boon to industrial drug discovery efforts, significantly improving the efficiency of natural product screening. At the same time, this approach will activate uncharacterized gene clusters in Photorhabdus and Xenorhabdus species, which will then be identified and characterized. These compounds are likely to have broad applications, as strains from these species are important biocontrol agents in agriculture (through their symbiotic relationship with insecticidal nematodes), as well as an underexplored source of antimicrobial compounds. The metabolites of Photorhabdus luminescens are of particular interest, as this bacteria is thought to be the causative agent behind “Angel’s Glow.” Soldiers injured in the Battle of Shiloh during the American Civil War reported that their wounds glowed in the dark, an unsettling effect that nevertheless appeared to prevent infection and aid healing. P. luminescens and its close relatives are the only known terrestrial bacteria to exhibit bioluminescence.