Microbial natural product discovery is often laborious. This paper introduces a novel workflow targeting alkyl halide-derived natural products by depleting halide anions from microbial growth media. Comparing metabolomes of bacteria grown in halide-replete and -deficient media led to the discovery of nostochlorosides, products of an orphan halogenase-encoding gene cluster from *Nostoc punctiforme*. These chlorinated glycolipids, featuring the rare sugar gulose, are polymerized via an unprecedented enzymatic etherification reaction. This highlights using biosynthetic logic to streamline natural product discovery.

Nathaniel R. Glasser, Dongtao Cui, Douglas D. Risser, C. Denise Okafor, Emily P. Balskus