Gene cluster activation in a bacterial symbiont leads to halogenated angucyclic maduralactomycins and spirocyclic actinospirols

Growth from spores activated a biosynthetic gene cluster in <i>Actinomadura</i> sp. RB29, resulting in the identification of two novel groups of halogenated polyketide natural products, named maduralactomycins and actinospirols. The unique tetracyclic and spirocyclic structures were assigned based on a combination of NMR analysis, chemoinformatic calculations, X-ray crystallography, and ¹³C labeling studies. On the basis of HRMS² data, genome mining, and gene expression studies, we propose an underlying noncanonical angucycline biosynthesis and extensive post-polyketide synthase (PKS) oxidative modifications.