Marine actinomycetes belonging to the genus Salinispora have proven to be a rich source of novel secondary metabolites including one compound (salinosporamide A) that is currently in clinical trials for the treatment of cancer. Despite extensive fermentation studies of S. tropica and S. arenicola, recent genome sequencing has revealed an abundance of novel biosynthetic gene clusters in both taxa whose products have yet to be discovered. This new information provides clear evidence that even these well-studied environmental bacteria continue to represent an important resource for natural product discovery. We have amassed a large collection of several thousand Salinispora isolates from numerous worldwide collection sites that produce distinct suites of secondary metabolites indicating that the overall breadth of biosynthetic diversity within the genus is far greater than previously recognized. We are now presented with a unique opportunity to combine the powerful techniques of genome sequence analysis, along with the ability to genetically manipulate Salinispora in the laboratory, to integrate bacterial genetics into the natural product drug discovery process. We therefore propose a comprehensive and multi-disciplinary program in which innovative genome mining techniques will be employed to effectively enhance the discovery of natural products from this new group of marine bacteria. To accomplish the broad goals outlined in this application, the Moore and Jensen laboratories have established a long-term collaboration that seamlessly integrates the complementary expertise of both research programs. We propose two major aims. First, we will isolate, characterize, and test for biological activity new natural products from S. tropica strain CNB-440 and S. arenicola CNS-205 discovered through bioinformatics-based, genome mining techniques. From our comprehensive genome sequencing and annotation of both strains, we have identified five orphan gene sets to explore that have a high probability to yield novel metabolites with promising biological properties and novel enzymatic mechanisms in natural product biosynthesis. Second, we will sequence and annotate draft genomes of four new Salinispora strains, including two phylotypes of the new species S. pacifica and two geographically and metabolically distinct S. arenicola strains, and mine them for the production of novel secondary metabolites.

Public Health Relevance

Natural microbial products occupy a central role in medicine by providing the majority of the antibiotics and anticancer agents employed in the clinic as well as important 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. By combining a new marine bacterial resource that has a proven track record in providing clinically relevant drug candidates together with a comprehensive natural product discovery approach that employs innovative analyses of microbial genome sequences and state of the art genetic manipulation, we aim to unlock the biosynthetic potential of a select group of bacteria and provide new compounds for biological testing. These molecules have the potential to be developed into new anticancer agents or antibiotics, or provide the structural motifs from which such drugs can be developed. 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 #
1R01GM085770-01A1
Application #
7731587
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Jones, Warren
Project Start
2009-08-01
Project End
2013-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
1
Fiscal Year
2009
Total Cost
$312,229
Indirect Cost
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
Machado, Henrique; Tuttle, Robert N; Jensen, Paul R (2017) Omics-based natural product discovery and the lexicon of genome mining. Curr Opin Microbiol 39:136-142
Larson, Charles B; Crüsemann, Max; Moore, Bradley S (2017) PCR-Independent Method of Transformation-Associated Recombination Reveals the Cosmomycin Biosynthetic Gene Cluster in an Ocean Streptomycete. J Nat Prod 80:1200-1204
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
Gallagher, Kelley A; Wanger, Greg; Henderson, Jane et al. (2017) Ecological implications of hypoxia-triggered shifts in secondary metabolism. Environ Microbiol 19:2182-2191
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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