Natural Product Genome Mining

Principal Investigator: 
Proposal Abstract: 
Bacteria belonging to the Order Actinomycetales, commonly called actinomycetes, account for  approximately 75% of the microbial natural products used in human therapy. While major  pharmaceutical companies have moved en masse away from natural products as a resource for small molecule drug discovery, it has recently become recognized that actinomycetes derived  from marine sources represent an important new source of structurally diverse natural products. 
In particular, marine actinomycetes belonging to the genus Salinispora have proven to be a rich  source of biologically active secondary metabolites including salinosporamide A, which recently  completed phase I clinical trials for the treatment of cancer. The compounds produced by this  chemically prolific genus span virtually all known biosynthetic classes and have led to the  characterization of a growing number of unprecedented biosynthetic paradigms. After more than 
two decades of extensive marine sampling, we have amassed a collection of more that 5,000 diverse Salinispora strains. This collection provides unprecedented opportunities to further explore the biosynthetic potential of this extraordinary taxon and to address fundamental questions about mechanistic biochemistry and the evolutionary processes that generate new structural diversity. Here we propose the continuation of a genome-mining project that was initiated less than four years ago to analyze six Salinispora genome sequences. 
 
This renewal application builds upon the productive collaboration established between the Moore (biosynthesis/genome mining), Jensen (bioinformatics/microbiology) and William Fenical (natural product chemistry) laboratories. In this renewal, we specifically address five major aims: 1) the bioinformatic analysis of 101 Salinispora genome sequences, 2) the genome guided isolation and characterization of new, biologically active Salinispora natural products, 3) the expression of Salinispora biosynthetic gene clusters by transformation-associated recombination cloning, 4) the activation of ‘silent’ biosynthetic pathways by regulatory manipulation, and 5) the biosynthetic analysis of the Salinispora mTOR inhibitor lymphostin. These aims address fundamentally important questions related to the diversity and distributions of secondary metabolite biosynthetic pathways in a well-defined taxon and the evolutionary processes that generate new small molecule diversity.
 
Start and End Date: 
August 2009 to July 2017
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