Exploration of salinamide biosynthesis unveils a new intermolecular acting thioesterase

Salinamides A and B are highly unusual bicyclic depsipeptides, originally isolated from the marine actinomycete Streptomyces sp. CNB091. Both salinamides A and B display potent topical anti-inflammatory activity and moderate antibiotic activity, which has recently been attributed to the binding of salinamide A to bacterial RNA polymerase. Despite the expansion of this family of natural products, through the isolation of various derivatives, and efforts to understand the biosynthetic origins of salinamides through isotope-labelling experiments, their biosynthesis has until now remained elusive.

We shall describe how the successful heterologous expression of salinamides was facilitated by the direct capture of the biosynthetic gene cluster from gDNA, which was achieved utilizing transformation associated recombination (TAR) cloning. This platform enabled the interrogation of salinamide biosynthesis in vivo and subsequently unveiled a highly unusual thioesterase domain with the ability to catalyze an intermolecular transesterification, representing a significant shift in the biosynthetic paradigm.