The oceans are home to extraordinary levels of microbial diversity, much of which has yet to be characterized. The focus of our research is to address fundamental questions about the diversity and distributions of specific groups of bacteria in the marine environment. These studies frequently target bacteria such as the actinomycetes, which are capable of producing biologically active secondary metabolites. The compounds produced by these bacteria represent an important resource for drug discovery and provide opportunities to explore the functional roles of secondary metabolites in marine systems. Our studies employ molecular as well as culture-dependent techniques and include the analysis of genome sequences to explore the ecology and evolution of marine bacteria. We apply phylogenetic techniques to understand the relationships among bacteria and to trace the evolutionary history of the genes they maintain, many of which are subject to horizontal gene transfer. In the case of secondary metabolism, we believe the acquisition of pathways responsible for the production of biologically active molecules provides a rapid method to outcompete other members of the community or expand to a new environmental niche. We are only beginning to understand the implications of these processes, but believe they play a critical role in the ecology and evolution of the bacteria we are studying. We are also keenly interested in developing improved, sequence-based approaches to natural product discovery and believe that next generation sequencing will open the door to the discovery of vast numbers of new secondary metabolites.
CURRENT PROJECTS
MICROBIAL DIVERSITY: We are applying molecular and culture-based approaches to assess the diversity of marine bacteria. These efforts include developing new cultivation techniques and describing new taxa. We are keenly interested in species concepts as they apply to bacteria and have been testing theory-based concepts on a model group of marine actinomycetes. We are studying the distribution of these groups over varying spatial scales to better understand the role of geographic isolation in the speciation process and defining functional traits that can be linked to ecological differences among co-occurring species.
GENOMICS: We are analyzing the genomes of select marine bacteria obtained in culture as part of our diversity studies. A major focus is on marine actinomycetes in the genus Salinispora. The goals of these studies are to delineate the genetic differences between closely related species, define the evolutionary processes that have contributed to diversification, identify genes that may be associated with ecological differences among species, and explore the mechanisms of marine adaptation in this model group of marine bacteria. These studies have been in collaboration with the Joint Genome Institute, Community Sequencing Program.
MOLECULAR GENETICS OF NATURAL PRODUCT BIOSYNTHESIS: We are studying the diversity and distribution of specific classes of biosynthetic genes in marine bacteria. A major aim of this research is to develop approaches to natural product discovery that capitalize on increased access to DNA sequence data and thereby improve the efficiency of the discovery process. The goals of these studies are to develop rapid methods for the identification of strains that possess novel secondary metabolite biosynthetic potential. To help meet this goal, we have developed a web tool called NaPDoS (Natural Product Domain Seeker) (npdomainseekers.ucsd.edu). NaPDoS provides an automated method to assess secondary metabolite gene richness and diversity in DNA or amino acid sequences derived from individual strains or metagenomes. The results can be used to prioritize strains or environments for natural product discovery efforts and identify new biosynthetic gene lineages, which can be explored for new mechanisms of secondary metabolite assembly. These studies ultimately provide insight into the evolutionary history of biosynthetic pathways relative to their host strains and help us to understand the evolutionary mechanisms driving secondary metabolite diversification.
CHEMICAL ECOLOGY: Marine plants, invertebrates and microorganisms produce biologically active secondary metabolites that can have significant but generally undefined effects on co-occurring organisms. We are currently addressing the ecological roles of microbial secondary metabolites in chemical defense and niche adaptation. Current studies include addressing the roles of redox-active secondary metabolites in adaptation to microaerophilic environments and biologically active compounds in chemical defense.
NATURAL PRODUCT DISCOVERY: We work collaboratively with natural product chemists on the discovery of novel secondary metabolites from marine microorganisms. This research has led to the discovery of more than 100 new structures including two compounds that are currently in clinical trials for the treatment of cancer. These compounds are salinosporamide A and a semi-synthetic derivative of the fungal metabolite halimide, both of which are being developed by Nereus Pharmaceuticals (www.nereuspharm.com).
NaPDoS: The Natural Product Domain Seeker (NaPDoS) is a new web tool we have just developed. The goals of this tool are to provide a rapid method to assess the diversity of secondary metabolite biosynthetic genes in genomic or metagenomic sequence data. It is designed for both those well versed in natural product biosynthesis as well as anyone interested in making a more informed interpretation of the secondary metabolite genes in their data set. The site includes a detailed overview and tutorial describing how the tool works.
Link to NaPDoS: (http://npdomainseeker.ucsd.edu)
FIELD WORK
Fiji:
We are currently working in Fiji as part of an NIH/Fogarty International Center (LINK) program called an International Cooperative Research Group (LINK). The aims of this program are to study the diversity of marine microbes in Fiji and to assess their ability to produce new secondary metabolites with a focus on diseases relevant to the host country.
California:
As part of a newly funded Center for Oceans and Human Health (website forthcoming), we have been collecting samples from the Southern California Bight with the aim of identifying the sources and sinks of halogenated organic compounds that are accumulating up the food chain. In addition, we have been collecting samples off Southern California and the Channel Islands to study the distributions and diversity of an unusual group of meroterpenoid producing bacteria.