Using microbial chemical signals for natural product discovery

Here, we present the first evidence of an alternative role for LCOs that involves trans-kingdom signaling between a fungus and multiple soilborne bacteria through the regulation of fungal-secreted metabolites with potential bioactivities. Altogether, metabolomics followed by network and transcriptomics analyses, highlight that the greatest increase in secondary metabolite production in A. fumigatus occurs in the presence of LCOs, followed by oleic acid and short-chained COs. Moreover, we found that fumagillin was the most consistently produced SMs across all treatments. Fumagillin is widely used in human medicine, particularly as a cancer treatment for its angiogenesis inhibitory properties49. Because LCOs were reported to cause angiogenesis in mammalian cells25, these results may support new therapeutic synergism between fumagillin production and LCO activity in cancer treatment. Finally, we observed that bacterial growth did not respond to low concentrations of exogenous LCOs, unlike plants2, fungi9, and mammalian cells25, suggesting that the perception of LCOs could be limited to eukaryotic organisms. Collectively, these results demonstrate that different types of LCOs and their precursors are distinguishably perceived by the fungus thus regulating its metabolome and governing its microbial and cellular communication. This study provides an approach to identify and characterize novel natural products not produced under standard culture conditions, which can have potential antibacterial properties against pathogenic bacteria, act as bio- activators promoting the growth of symbiotic bacteria, or act as therapeutic agents for cancer treatments.

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