The Sandarazols are Cryptic and Structurally Unique Plasmid-Encoded Toxins from a Rare Myxobacterium*.

Abstract

Herein, 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 the production and subsequent isolation and structure elucidation of novel secondary metabolites, the sandarazols A–G. The sandarazols contain intriguing structural features and very reactive functional groups 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 biosynthetic 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 sandarazols’ potential function as defensive secondary metabolites or toxins.