Targeted Discovery of β-Branched Conjugated Polyketides from Bacteria Based on Genomic and Metabolomic Hallmarks

A logical discovery method based on metabologenomic targeting was designed to search for new β-branched conjugated polyketides. PCR screening of a bacterial DNA library (1,638 strains) targeting the key enzyme hydroxymethylglutaryl-CoA synthase (HCS) homolog-encoding gene as a genomic hallmark identified 67 hit strains. Phylogenetic analysis of HCS homolog-encoding gene amplicons prioritized strains potentially producing new β-branched conjugated polyketides. Vibronic fine structures in ultraviolet spectra as a metabolomic hallmark clearly identified β-branched conjugated polyketides in bacterial extracts, logically leading to the discovery of paenillaene (1), paeniformicins A–D (2–5) from two strains belonging to the relatively unexplored genus Paenibacillus, and pulvomycins E–F (6–7) from a Streptomyces strain. Combined analysis of spectroscopic data, chemical reactions, quantum mechanics-based calculations, and biosynthetic gene clusters led to the structure elucidations of 1–7 as new β-branched conjugated polyketides. Paenillaene (1) dissociated amyloid-β aggregates, paeniformicin D (5) showed significant anti-tubercular activity against Mycobacterium tuberculosis, and pulvomycin E (6) displayed remarkable anti-proliferative activity against several human cancer cells, including a docetaxel-resistant breast cancer cell line. This metabologenomic targeting method provides an efficient tool for systematic discovery of new bioactive β-branched conjugated polyketides.