Discovery Biosynthesis Subgroup

Many extraordinarily useful small molecules are either natural products or can trace their origins to natural products.

Between the years of 2000 – 2010, 75% of all approved antibiotic new chemical entities were natural products or natural product-derived. Indeed, despite greatly reduced efforts of the pharmaceutical industry towards natural product discovery, fully 50% of approved new chemical entities in all areas of medicinal chemistry were natural product-derived during this time period. A large fraction of natural products have been mined from microorganisms that were isolated from the soil. A few examples of antimicrobial compounds produced by soil actinobacteria include b-lactams such as penicillins/ cephalosporins and clavulanic acid, macrolides such as erythromycins and amphotericins, peptides such as daptomycin and vancomycin, aromatic polyketides such as tetracycline and daunomycin, and the many aminoglycosides such as kanamycin, and tobramycin.

The VLBS has pioneered the hypothesis that cave microenvironments create specialized microbial habitats unique to the geology and geochemistry of the region in which they are located, and distinct from their surface counterparts. Furthermore, we hypothesize that the microorganisms living in these hypercompetitive environments will produce a wide variety of cave-specific natural products as defensive, predatory and signaling tools. Our survey of cave microorganism diversity and secondary metabolic fecundity has illuminated the considerable potential of the cave ecosystem for natural product discovery. We established that actinobacteria are abundant and isolable from cave ecosystems and are prolific producers of secondary metabolites. A video outline of this project can be found in a documentary on the Bachmann/McLean project produced by the American Museum of Natural History, which became part of their ‘Hall of Biodiversity’ exhibit in New York in winter 2014. Watch a short video documentary here.

The other primary focus of the Discovery group is centered in the burgeoning field of ‘genome mining’. It has recently become apparent, due to genome sequencing, that the microbial producers of natural products have far more potential than originally thought. Microorganism that have been mined for drugs generally yield one or two new drugs, but the genome reveals that they contain the blueprints for making dozens of different new potential bioactive compounds. However, what is not know is how to ‘turn on’ these blueprints to access the molecular diversity. The VLBS has a major focus of activating and discovering this cryptic silent metabolism. To accomplish this we have created, in collaboration with the group of Prof. John McLean, new tools for studying how bacteria respond to stimulus at the metabolome scale – that is tracking how every molecule in a cell responds to stimulus. Stimulus includes microbial challenge (we call bacterial fight club), exposure to antibiotic challenge, and exposure to toxins and other environmental insults. We have adapted a ‘big data’ approach to mining the metabolome for the products of microbial stimulus and the results to date have been stunning. Not only are we discovering new natural products by this stimulation – big data approach, but we are learning fundamental new knowledge about how microbes respond to environmental challenge at a chemical biological level. Representative publications from this new work are now appearing in high impact journals.