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 than 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.

Public Health Relevance

Natural microbial compounds occupy a central role in medicine. They provide the majority of the antibiotics and anticancer agents employed in the clinic and the biomedical research tools used to discover and probe cellular processes. As the discovery rate of new chemical entities from bacteria diminishes over time, innovative methods are urgently needed to provide new molecular scaffolds from which drug leads can be developed. Our discovery of the genus Salinispora as a major bacterial source of novel bioactive molecules has fueled a comprehensive genomics-based drug discovery program aimed at providing new compounds for biological testing. Public health may directly benefit from these discoveries or, in the long term, from advances in the efficiency of the natural product discovery process that will be gained from this research.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM085770-05
Application #
8579584
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Gerratana, Barbara
Project Start
2009-08-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$319,300
Indirect Cost
$113,300
Name
University of California San Diego
Department
Zoology
Type
Schools of Earth Sciences/Natur
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Amos, Gregory C A; Awakawa, Takayoshi; Tuttle, Robert N et al. (2017) Comparative transcriptomics as a guide to natural product discovery and biosynthetic gene cluster functionality. Proc Natl Acad Sci U S A 114:E11121-E11130
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Letzel, Anne-Catrin; Li, Jing; Amos, Gregory C A et al. (2017) Genomic insights into specialized metabolism in the marine actinomycete Salinispora. Environ Microbiol 19:3660-3673
Zhang, Jia Jia; Tang, Xiaoyu; Zhang, Michelle et al. (2017) Broad-Host-Range Expression Reveals Native and Host Regulatory Elements That Influence Heterologous Antibiotic Production in Gram-Negative Bacteria. MBio 8:
Millán-Aguiñaga, Natalie; Chavarria, Krystle L; Ugalde, Juan A et al. (2017) Phylogenomic Insight into Salinispora (Bacteria, Actinobacteria) Species Designations. Sci Rep 7:3564
Patin, Nastassia V; Schorn, Michelle; Aguinaldo, Kristen et al. (2017) Effects of Actinomycete Secondary Metabolites on Sediment Microbial Communities. Appl Environ Microbiol 83:
Crüsemann, Max; O'Neill, Ellis C; Larson, Charles B et al. (2017) Prioritizing Natural Product Diversity in a Collection of 146 Bacterial Strains Based on Growth and Extraction Protocols. J Nat Prod 80:588-597
Floros, Dimitrios J; Jensen, Paul R; Dorrestein, Pieter C et al. (2016) A metabolomics guided exploration of marine natural product chemical space. Metabolomics 12:

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