There is societal need for new compounds in our arsenal of defenses against microbial pathogens, many of which are increasingly resistant to existing therapeutics. The best possible source for new antimicrobial compounds with potentially novel mechanisms of action is within natural environments, particularly soils, which have the greatest diversity of microbial life. This research proposal advances the science of metagenomics, the cloning of DNA from entire microbial communities, to discover novel antibiotics and identify the best lead candidates for clinical development. Scientists at Lucigen Corporation and Auburn University have combined key technological breakthroughs that result in an improved paradigm for screening metagenomic libraries for small molecules. A major rate limiting step in this process is the millions of bioassays required to screen natural product libraries for small molecules with bioactivity. This Phase I SBIR will develop new tools for massively parallel next-generation sequencing and analysis of the metagenomic libraries to discover natural product pathways in silico. The process will accelerate natural product chemistry discovery fifty-fold while eliminating the bias of biological assays. The successful outcome of this research will also revolutionize the ability to completely analyze complex genomes of significant nutritional and medical value to humans.
In the fight against microbial infectious diseases we are losing ground due to the development of antibiotic resistance and our inability to find replacement drugs. The loss of life and the burden of treatment is a significant public health threat to American citizens. The proposed research unleashes a new set of tools for drug discovery that permits access to the entire diversity of microbial life in soils and other environments. Our next-generation metagenomic approach will dramatically accelerate the process of identifying novel pathways that synthesize antibiotic and other compounds of medicinal value.