Key to the process of pharmaceutical lead compound discovery from natural sources is the effective access and characterization of highly diverse molecular structures. In this regard, exploration of the marine environment for bioactive natural products is revealing new vistas in natural products chemical diversity. In this application we propose the development of innovative technologies and knowledge, principally based on LC-MS/MS data and 'molecular mapping', which will improve the effectiveness of natural products drug discovery efforts. This will enable a much improved capacity to discover new molecular diversity or analogs in desired structure classes. We will develop an understanding of the degree of expression of natural product pathways in cultured strains, and will develop novel methods by which to upregulate low or non-expressing biosynthetic gene clusters. As a result of these studies, new marine cyanobacterial natural products will be discovered and their biomedical properties will be characterized. To accomplish these goals we have the following four specific aims: 1) To use LC-MS/MS profiling of cyanobacterial extracts and pure compounds, followed by molecular mapping, to create a representation of the chemical universe of our samples. 2) To use QPCR and genome sequencing technologies to evaluate the degree of expression of natural product pathways in our cultured marine cyanobacteria, and to connect Natural Product Super-producing strains of cyanobacteria with their genotypes. This latter information can be used to find genetic markers that can be rapidly deployed to locate this phenotype in new cyanobacterial cultures and collections. 3) To use a suite of imaginative methods to transcriptionally activate cryptic natural product biosynthetic gene clusters in strains determined in Aim 2 to possess un-expressed natural products capacity, and to analyze the resulting elicited secondary metabolomes by mass spectrometry and molecular mapping. 4) To isolate members of new families of compounds detected in Aims 1, as well as newly expressed natural products from Aim 3, and rigorously establish molecular structures using advanced analytical methods. Through the course of these four specific aims, this collaborative group will explore a number of innovative methods and approaches in the natural products sciences, including MS/MS molecular mapping, genomic analysis of natural products expression, elicitation of new natural products expression, connection of natural product-rich phenotypes to their corresponding genotypes, imaging mass spectrometry of complex consortiums of species wherein natural product pathways are activated, and novel automated MS approaches to natural products characterization. All of these methods are focused on improving the detection and characterization of the molecular diversity present in microorganisms, in this case, marine cyanobacteria. This molecular diversity continues to be an important source of inspirational molecules for biomedical research and drug discovery.

Public Health Relevance

Natural products continue to be very important sources of new drug leads as well as research biochemicals. The quality and success of these efforts depends on the effective access to the enormous chemical diversity present in the natural world. This application proposes the development of several innovative new methods and approaches in the natural products sciences, such as characterizing the universe of cyanobacterial secondary metabolites using molecular maps created from mass spectrometric data. These advances will improve the effectiveness of natural products drug discovery investigations in diverse therapeutic areas.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Gerratana, Barbara
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University of California San Diego
Schools of Earth Sciences/Natur
La Jolla
United States
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