At a time when pharmaceutical pipelines of new efficacious chemotypes remain critically low, and it is estimated that dozens of species are going extinct daily, it is essential that available repositories of biologically active natural products be assembled and mined as fully as modern technologies allow to assess the potential of these natural products as pharmaceutical leads or molecular research tools. The objectives of this application are to leverage and expand an archive of South African tunicates (ascidians) at the South African Institute of Aquatic Biodiversity (SAIAB), and the extensive resources for marine collections of the South African Environmental Observatory Network (SAEON), to investigate the potential of natural products from South African tunicates and their microbiota as molecular probes and leads for application in cancer and infectious diseases. This opportunity supports international exchange and training of students in interdisciplinary natural products research. The temperate southeastern coast of South Africa exhibits an unprecedented abundance and diversity of largely unstudied filter-feeding tunicates, which house complex microbial consortia. Our central hypothesis is that biologically diverse and endemic South African tunicates, not found elsewhere, are a particularly valuable source of biologically active new chemotypes. Guided by preliminary data that includes isolation of new metabolites with potent biological activities, two specific aims will be pursued:
In aim 1, a chemical library of tunicate extracts and fractions will be systematically assembled and associated with biological (cytotoxicity, anti-bacterial and anti-viral) and chemical (LC-MS/MS and 1H NMR) profiles. Biological testing will include functional assays for inhibition of protein secretion in both eukaryotes (targeting cotranslational translocation at the endoplasmic reticulum) and prokaryotes (inhibition of Type II Secretion-mediated virulence), and inhibition of viral entry into cells.
In aim 2, purification and structure elucidation of new biologically active natural products, with a focus on cancer activity, from prioritized samples will facilitate secondary biological investigation that will support future molecular mechanism of action studies. In addition to new pharmaceutical leads and molecular research tools, and new chemical entities for potential development of new synthetic methodologies, this research is expected to provide a ?documented? library of extracts coupled to a biological archive for a collection of up to 200 different South African tunicates. Integration of these data with microbial phylogenetics profiles of the source tunicates will allow observation of chemotaxonomic, ecological and geographical pattern, and guide future targeted metagenomic analyses of microbial symbiont populations for biosynthetic investigations.
The current rate of extinction of species rivals that during the period of dinosaur extinction 65 million years ago, making inventory of biological diversity that may be relevant to human health a priority. Marine sessile filter-feeding organisms that house complex microbial communities have yielded exceptionally diverse new natural products, which serve as tools to understand and ultimately treat diseases (e.g. anticancer agents Yondelis and Halaven). Characterization of structurally unusual new tunicate- derived natural products as potent cytotoxins, anti-virals or inhibitors of virulence in multi-drug resistant bacterial pathogens will contribute to the development of efficacious therapeutic approaches.
| Nazari, Mohamad; Serrill, Jeffrey D; Wan, Xuemei et al. (2017) New Mandelalides Expand a Macrolide Series of Mitochondrial Inhibitors. J Med Chem 60:7850-7862 |
