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

Area of Science:

• Microbiology
• Natural Product Chemistry
• Genomics

Background:

• Nocardia are opportunistic pathogens causing difficult-to-treat infections.
• Few natural products are known from Nocardia, despite their relation to Streptomyces.
• The role of Nocardia-derived natural products in pathogenesis is largely unknown.

Purpose of the Study:

• To investigate the biosynthetic capacity of pathogenic Nocardia.
• To identify and characterize novel bioactive natural products from Nocardia.
• To elucidate the genetic basis of natural product biosynthesis in Nocardia.

Main Methods:

• Chemical analysis of Nocardia terpenica isolates.
• Genomic sequencing and analysis of biosynthetic gene clusters.
• Construction and analysis of transposon mutant libraries in Nocardia.
• Molecular microbiology techniques to link genes to molecules.

Main Results:

• Discovery and characterization of terpenomycin, a novel cytotoxic and antifungal polyene.
• Identification of the polyketide synthase (PKS) responsible for terpenomycin biosynthesis.
• Unveiling unusual features in the PKS, including split, skipped, and iterative modules, and methoxymalonate as a starter unit.
• Generation of a terpenomycin-null mutant by inactivating the identified PKS.

Conclusions:

• Neglected actinomycetes like Nocardia possess significant, unappreciated potential for producing diverse bioactive molecules.
• Unique biosynthetic pathways for natural products exist in Nocardia and warrant further investigation.
• Nocardia terpenica is a source of novel natural products with potential therapeutic applications.