New Nat. Chem. Paper by the Piel Lab
Genome-based discovery and total synthesis of janustatins, potent cytotoxins from a plant-associated bacterium
Reiko Ueoka, Philipp Sondermann, Stefan Leopold-Messer, Yizhou Liu, Rei Suo, Agneya Bhushan, Lida Vadakumchery, Ute Greczmiel, Yoko Yashiroda, Hiromi Kimura, Shinichi Nishimura, Yojiro Hoshikawa, Minoru Yoshida, Annette Oxenius, Shigeki Matsunaga, R Thomas Williamson, Erick M Carreira, Jörn Piel
Nat Chem. 2022 Sep 5.
Host-associated bacteria are increasingly being recognized as underexplored sources of bioactive natural products with unprecedented chemical scaffolds. A recently identified example is the plant-root-associated marine bacterium Gynuella sunshinyii of the chemically underexplored order Oceanospirillales. Its genome contains at least 22 biosynthetic gene clusters, suggesting a rich and mostly uncharacterized specialized metabolism. Here, in silico chemical prediction of a non-canonical polyketide synthase cluster has led to the discovery of janustatins, structurally unprecedented polyketide alkaloids with potent cytotoxicity that are produced in minute quantities. A combination of MS and two-dimensional NMR experiments, density functional theory calculations of 13C chemical shifts and semiquantitative interpretation of transverse rotating-frame Overhauser effect spectroscopy data were conducted to determine the relative configuration, which enabled the total synthesis of both enantiomers and assignment of the absolute configuration. Janustatins feature a previously unknown pyridodihydropyranone heterocycle and an unusual biological activity consisting of delayed, synchronized cell death at subnanomolar concentrations.