Discovery and Biosynthesis of the Cytotoxic Polyene Terpenomycin in Human Pathogenic Nocardia

Nocardia are opportunistic humanpathogens that can cause a range of debilitating and difficult totreat infections of the lungs, brain, skin, and soft tissues. Despitetheir close relationship to the well-known secondary metabolite-producinggenus, Streptomyces, comparativelyfew natural products are known from the Nocardia, and even less is known about their involvement in the pathogenesis.Here, we combine chemistry, genomics, and molecular microbiology toreveal the production of terpenomycin, a new cytotoxic and antifungalpolyene from a human pathogenic Nocardia terpenica isolate. We unveil the polyketide synthase (PKS) responsible forterpenomycin biosynthesis and show that it combines several unusualfeatures, including "split", skipped, and iterativelyused modules, and the use of the unusual extender unit methoxymalonateas a starter unit. To link genes to molecules, we constructed a transposonmutant library in N. terpenica, identifyinga terpenomycin-null mutant with an inactivated terpenomycin PKS. Ourfindings show that the neglected actinomycetes have an unappreciatedcapacity for the production of bioactive molecules with unique biosyntheticpathways waiting to be uncovered and highlights these organisms asproducers of diverse natural products.