NIH Research Festival
Bacterial natural products are a varied and rich source of undiscovered anti-tuberculosis (TB) drugs with unique scaffolds and/or novel mechanisms of action. Due to the threats of increasing TB drug resistance, we are in urgent need of new drugs to treat the disease. Sphagnum peat bogs are acidic and hypoxic environments, conditions similar to those encountered in tuberculous granulomas. Moreover, these habitats are major natural reservoirs of mycobacterial and competing species. These factors support sphagnum peat bogs as ideal sources of antitubercular compounds. Here we report novel compounds from bog bacteria capable of selectively inhibiting M. tuberculosis. Bog bacteria, including Pedobacter, Pantoea, Pseudomonas, Chryseobacterium, Streptomyces, Burkholderia and Variovorax were found to produce secondary metabolites active against M. tuberculosis. Two positive hits, identified as Variovorax paradaxus and Chryseobacterium sp., were selected for whole genome sequencing based on scarce prior reports of associated natural products and exclusive and potent activity of the active agents against M. tuberculosis (MIC 100 µg/ml). Three novel non-ribosomal peptide (NRP) or hybrid NRP/polyketide (PK) biosynthetic gene clusters were identified for V. paradaxus, and one PK for Chryseobacterium sp. Based on the in silico predict structure, bioactivity-guided fractionation and spectrometric tools, two new compounds were identified. Our findings indicate that two novel compounds with unique scaffolds and/or novel mechanisms of action can be fully isolated and characterized from V. paradaxus and Chryseobacterium sp. These compounds have the potential to form a basis for new anti-TB classes addressing bacterial targets that are currently underexploited.
Scientific Focus Area: Microbiology and Infectious Diseases
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