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Biosynthesis of fragin is controlled by a novel quorum sensing signal

C. Jenul,Simon Sieber,Christophe Daeppen,Anugraha Mathew,Martina Lardi,Gabriella Pessi,D. Hoepfner,M. Neuburger,A. Linden,K. Gademann,L. Eberl

Published 2018 in Nature Communications

ABSTRACT

Members of the diazeniumdiolate class of natural compounds show potential for drug development because of their antifungal, antibacterial, antiviral, and antitumor activities. Yet, their biosynthesis has remained elusive to date. Here, we identify a gene cluster directing the biosynthesis of the diazeniumdiolate compound fragin in Burkholderia cenocepacia H111. We provide evidence that fragin is a metallophore and that metal chelation is the molecular basis of its antifungal activity. A subset of the fragin biosynthetic genes is involved in the synthesis of a previously undescribed cell-to-cell signal molecule, valdiazen. RNA-Seq analyses reveal that valdiazen controls fragin biosynthesis and affects the expression of more than 100 genes. Homologs of the valdiazen biosynthesis genes are found in various bacteria, suggesting that valdiazen-like compounds may constitute a new class of signal molecules. We use structural information, in silico prediction of enzymatic functions and biochemical data to propose a biosynthesis route for fragin and valdiazen. Fragin is a diazeniumdiolate metabolite with antifungal activity, produced by some bacteria. Here, Jenul et al. show that metal chelation is the molecular basis of fragin’s antifungal activity, and that a gene cluster directing fragin biosynthesis is also involved in the synthesis of a signal molecule.

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