Discovery and Biosynthesis of Glycosylated Cycloheximide from a Millipede-Associated Actinomycete

Journal of Natural Products
2023.0

Abstract

Chemical redundancy of microbial natural products (NPs) underscores the importance to exploit new resources of microorganisms. Insect-associated microbes are prolific but largely underexplored sources of diverse NPs. Herein, we discovered the new compound <i>α</i>-l-rhamnosyl-actiphenol (<b>1</b>) from a millipede-associated <i>Streptomyces</i> sp. ML6, which is the first glycosylated cycloheximide-class natural product. Interestingly, bioinformatics analysis of the ML6 genome revealed that the biosynthesis of <b>1</b> involves a cooperation between two gene clusters (<i>chx</i> and <i>rml</i>) located distantly on the genome of ML6. We also carried out <i>in vitro</i> enzymatic glycosylation of cycloheximide using an exotic promiscuous glycosyltransferase BsGT-1, which resulted in the production of an additional cycloheximide glycoside cycloheximide 7-<i>O</i>-<i>β</i>-d-glucoside (<b>5</b>). Although the antifungal and cytotoxic activities of the new compounds <b>1</b> and <b>5</b> were attenuated relative to those of cycloheximide, our work not only enriches the chemical repertoire of the cycloheximide family but also provides new insights into the structure-activity relationship optimization and ecological roles of cycloheximide.

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