Natural products profoundly impact many research areas,
including
medicine, organic chemistry, and cell biology. However, discovery
of new natural products suffers from a lack of high throughput analytical
techniques capable of identifying structural novelty in the face of
a high degree of chemical redundancy. Methods to select bacterial
strains for drug discovery have historically been based on phenotypic
qualities or genetic differences and have not been based on laboratory
production of secondary metabolites. Therefore, untargeted LC/MS-based
secondary metabolomics was evaluated to rapidly and efficiently analyze
marine-derived bacterial natural products using LC/MS-principal component
analysis (PCA). A major goal of this work was to demonstrate that
LC/MS-PCA was effective for strain prioritization in a drug discovery
program. As proof of concept, we evaluated LC/MS-PCA for strain selection
to support drug discovery, for the discovery of unique natural products,
and for rapid assessment of regulation of natural product production.
Bioassay-guided metabolomic analyses led to the characterization of four new 20-membered glycosylated polyketide macrolactams – macrotermycins A-D – from a termite-associated actinomycete, Amycolatopsis sp. M39. M39’s sequenced genome revealed the macrotermycin’s putative biosynthetic gene cluster. Macrotermycins A and C had antibacterial activity against human-pathogenic S. aureus and of greater ecological relevance, they also had selective antifungal activity against a fungal parasite of the termite fungal garden.
GilOII has been unambiguously identified as the key enzyme performing the crucial C-C bond cleavage reaction responsible for the unique rearrangement of a benz[a]anthracene skeleton to the benzo[d]naphthopyranone backbone typical for the gilvocarcin type natural anticancer antibiotics. Further investigations of this enzyme led to the isolation of a hydroxy-oxepinone intermediate which allowed important conclusions regarding the cleavage mechanism.
Microtermolides A (1) and B (2) were isolated from a Streptomyces sp. strain associated with fungus-growing termites. The structures of 1 and 2 were determined by 1D- and 2D-NMR spectroscopy and high-resolution mass spectrometry. Structural elucidation of 1 led to the re-examination of the structure originally proposed for vinylamycin (3). Based on a comparison of predicted and experimental 1H and 13C NMR chemical shifts, we propose that vinylamycin’s structure be revised from 3 to 4.
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