A Metabologenomics Platform for Large Scale High Throughput Natural Product Discovery

ABSTRACT The estimates of natural product producing gene clusters within the genomes of microorganisms are far greater than the number of known natural products indicating that there is a wealth of untapped molecules within these organisms that offer huge potential as leads for new medicines Unfortunately the prevailing paradigms for natural product discovery are ill suited for accessing this bounty of molecules providing a rate of discovery that is unacceptable in the modern era There is therefore a significant gap between the potential of microorganisms to deliver new natural products and our ability to access this potential effectively To bridge this gap Microbial Pharmaceuticals is developing the next generation technology that will deliver unparalleled access to these compounds and the means by which they can be characterized and put to use The long term goal of Microbial Pharmaceuticals is to provide a complete roadmap of secondary metabolism within actinobacteria known to produce the greatest numbers of natural products by conducting metabologenomic screening of different strains The data generated from this process will provide all expressed metabolites and their coupled biosynthetic gene clusters while the large scale of this effort will overcome the cryptic gene cluster problem faced by approaches that only investigate a few strains Microbial Pharmaceuticals will optimize our metabologenomics data acquisition platform Aim and simultaneously improve upon our correlation algorithms Aim Optimization of the platform to allow rapid and reproducible data acquisition will be achieved using UPLC and high mass accuracy mass spectrometry with the goal of decreasing cost and increasing the rate of acquisition Aim a This process will be piloted on new bacterial strains and the data incorporated into a database of known and new natural products Aim b The successful outcome of Aim during Phase I will lay the significant groundwork to achieve our long term future goal of screening strains cheaply and efficiently We will also implement an MS networking feature into the metabologenomics database Aim The combination of metabologenomic data from the strains investigated coupled to the improved correlations will provide a plethora of new molecules that may be accessed in a deterministic fashion By operating in a fundamentally new modus operandi a steady stream of high value compounds will emerge which have been honed by nature over millennia for activity in complex biological systems Project Narrative The proposed research will significantly advance public health because it provides a new technology for the large scale and high throughput discovery of new natural products that have untapped potential for treating human diseases This goal will be achieved by developing an innovative approach combining contemporary methods of genomics metabolomics and bioinformatics to elucidate natural molecules from bacteria a rich source of currently used medicines on a scale never before seen