Discovery of Novel Anti-Tuberculosis Drugs from Sphagnum Bog Bacteria

Authors

• M Espinoza-Moraga
• HI Boshoff
• CE Barry 3rd

Abstract

Globally, tuberculosis (TB) causes around 1.4 million deaths annually. It is estimated that one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), the pathogen that causes TB. Due to the growing threat of anti-TB drug resistance, we are in urgent need of new drugs to treat the disease. Sphagnum peat bogs are acidic and hypoxic environments, with similar conditions to those encountered in tuberculous granulomas. Moreover, these habitats are also major natural reservoirs of mycobacterial species. Natural selection has endowed other microorganisms living in these nutrient-bare sphagnum areas with the ability to compete with endogenous slow-growing mycobacteria for these scarce nutrients by secreting secondary metabolites. These factors support sphagnum peat bogs as ideal sources for discovery of novel anti-TB drugs. Sphagnum bog samples were collected across Northeastern US. Bog bacteria, including Chryseobacterium, Variovorax, Pedobacter, and Pantoea were found to produce secondary metabolites against Mtb. These positive hits were selected for whole genome sequencing based on scarce prior reports of their natural products and their exclusive, potent activity against Mtb (MIC 100 µg/ml). No cytotoxicity against HepG2 cells was observed for these metabolites (IC50 >100 µg/ml). Novel biosynthetic gene clusters, including non-ribosomal peptide (NRP), polyketide (PK) and/or hybrid NRP/PK among others, were identified using automated bioinformatics software PRISM and anti-SMASH 3.0. Based on the in silico predict structure, bioactivity-guided fractionation of bacterial biomass samples and LC-MS analysis, novel compounds were identified. Subsequent transcriptional profiling of Mtb treated with these metabolites along with reporter and macromolecular incorporation assays yielded signatures indicating novel mechanisms of action beyond DNA damage and cell wall disruption (current pipeline of anti-TB drugs). Currently, compounds with unique scaffolds and novel mechanisms of action are being fully isolated and characterized. These compounds have the potential to form a basis for new anti-TB classes addressing bacterial targets that are currently underexploited. Our findings highlight the benefits of searching bog environments for new species that make natural products with potent, exclusive anti-TB activity. These metabolites could bypass resistance and form the foundation of new therapies.

Scientific Focus Area: Microbiology and Infectious Diseases

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