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.
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.
|Zhang, Jia Jia; Moore, Bradley S; Tang, Xiaoyu (2018) Engineering Salinispora tropica for heterologous expression of natural product biosynthetic gene clusters. Appl Microbiol Biotechnol 102:8437-8446|
|Reynolds, Kirk A; Luhavaya, Hanna; Li, Jie et al. (2018) Isolation and structure elucidation of lipopeptide antibiotic taromycin B from the activated taromycin biosynthetic gene cluster. J Antibiot (Tokyo) 71:333-338|
|Schlawis, Christian; Kern, Simone; Kudo, Yuta et al. (2018) Structural Elucidation of Trace Components Combining GC/MS, GC/IR, DFT-Calculation and Synthesis-Salinilactones, Unprecedented Bicyclic Lactones from Salinispora Bacteria. Angew Chem Int Ed Engl 57:14921-14925|
|Bruns, Hilke; Crüsemann, Max; Letzel, Anne-Catrin et al. (2018) Function-related replacement of bacterial siderophore pathways. ISME J 12:320-329|
|Gallagher, Kelley A; Wanger, Greg; Henderson, Jane et al. (2017) Ecological implications of hypoxia-triggered shifts in secondary metabolism. Environ Microbiol 19:2182-2191|
|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|
|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|
|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:|
|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|
|Millán-Aguiñaga, Natalie; Chavarria, Krystle L; Ugalde, Juan A et al. (2017) Phylogenomic Insight into Salinispora (Bacteria, Actinobacteria) Species Designations. Sci Rep 7:3564|
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