Abstract
Soil dwelling bacteria such as myxobacteria defend themselves by using secondary metabolites to inhibit growth of competing microorganisms. In this work we describe a new plasmid found in Sandaracinus sp. MSr10575 named pSa001 spanning 209.7 kbp that harbors a cryptic secondary metabolite biosynthesis gene cluster (BGC). Activation of this BGC by homologous recombination mediated exchange of the native promoter sequence against a vanillate inducible system led to production and subsequent isolation and structure elucidation of novel secondary metabolites, the sandarazols A-G. The sandarazol structure contains intriguing features such as an α-chlorinated ketone, an epoxyketone and a (2R)-2-amino-3- (N,N-dimethylamino)-propionic acid building block. In depth investigation of the underlying biosynthetic machinery led to a concise biosynthetic model for the new compound family, including several uncommon biosynthesis steps. The chlorinated congener sandarazol C shows an IC50 value of 0.5 µM against HCT 116 cells and a MIC of 14 µM against Mycobacterium smegmatis, which points at the sandarazol’s potential function as defensive secondary metabolites or toxins. The sandara-zols’ BGC location on pSa001 is one of the very few example of large multimodular BGCs on a replicative plasmid, whose existence points at the mechanism of horizontal gene transfer events of entire multimodular BGCs to exchange chemical warfare capabilities between bacterial species.
Competing Interest Statement
The authors have declared no competing interest.
