Nature's combinatorial chemistry: A DNA based approach for harnessing nature's molecular diversity
Natural products are the source of the majority of FDA approved drugs. One of the key revelations to arise from the large-scale sequencing of bacterial genomic DNA is that traditional methods used for the discovery of natural products only provide access to a small fraction of the natural product biosynthetic gene clusters present in nature. Soil microbes that have not yet been cultured outnumber their cultured counterparts by at least two to three orders of magnitude. The uncultured majority no doubt produces small molecules that could serve as therapeutic agents however there are currently no general strategies for accessing the molecules produced by these organisms. This proposal outlines a DNA-based strategy for the discovery and characterization of natural products from uncultured bacteria. In short, biosynthetic pathways that contain genes encoding enzymes involved in the biosynthesis of pharmacologically active or privileged natural product substructures (i.e. ~-lactams, lanthionines, thiazoles, C-0-C coupled aromatic amino acids and specific polyketide substructures) will be cloned from communities of uncultured bacteria and expression of these pathways in model microbial systems will be used to gain access to the molecules they encode. Compounds discovered using this strategy should show a high frequency of biological activity because
each will have at least one structural feature that has a history of being associated with biological activity. Having the ability to examine the biosynthetic capacity of naturally occurring bacteria populations, instead of just the small fraction that are easily cultured, should significantly increase the likelihood of finding metabolites with new chemical structures, new biological activities and novel mechanisms of avoiding resistance. The methods outlined in this proposal will facilitate the discovery of new biologically active natural products from many previously inaccessible biosynthetic gene clusters.
Arnold O. Beckman exemplifies the meaning of the word humanitarian. Combined with his unwavering enthusiasm for life, his keen sense of humor and his strong moral and ethical principles, he is a national icon.