South African Natural Products Research

In collaboration with Microbiology Professor Rosemary Dorrington of Rhodes University, and tunicate (ascidian/sea squirt) taxonomist Shirley Parker-Nance, we investigate the unprecedented abundance, diversity and endemism of tunicates on the East Cape coast of South Africa, where the Indian and Atlantic Oceans mix. Our long term collaborative research goal is to leverage and expand the archive of South African marine invertebrates at the South African Institute of Aquatic Biodiversity (SAIAB), the biodiversity inventory program of the South African Environmental Observation Network (SAEON), and a biological screening initiative recently launched at RU by the South African Medical Research Council, to investigate the potential of natural products (NPs) from South African marine organisms and their microbiota as molecular probes and leads for developing new cancer and infectious disease therapies.

The Chemistry of South African Didemnid Tunicates and their Microbial Consortia

In collaboration with Microbiology Professor Rosemary Dorrington of Rhodes University, and tunicate (ascidian/sea squirt) taxonomist Shirley Parker-Nance, we investigate the unprecedented abundance, diversity and endemism of tunicates on the East Cape coast of South Africa, where the Indian and Atlantic Oceans mix. Our focus is on a growing archive of unusual “gelatinous” didemnids, typified by the striking morphology of the mandelalide-producer (Lissoclinum mandelai). In addition to discovery of new biologically active NPs, our goal is to characterize the microbial consortia these tunicates using phylogenetics, metagenomics, and laboratory-based microbial culturing as appropriate, cultivating collaboration with South African and U.S. researchers.

The Role of Chemical Signaling in the Microbial Ecology of Living Stromatolites

The term “stromatolite” is generally recognized to refer to the earliest known fossils of cyanobacterial-rich sedimentary deposits formed by the metabolic activity of microbial communities, from the Archaean and Precambrian eras. These have been of intense geobiological and geochemical interest with regard to theories on the origin of life, and also bio-mineralization and lithification as related to global carbon cycling.

A three-pronged approach integrating collaborative multidisciplinary strategies has been conceived to investigate of South African stromatolite beds to explore the extent, signifying potential importance/role, of small molecule chemical signaling between microorganisms in microbial consortia during the processes of stromatolite formation, maturation and persistence. This is enabled by gathering expert collaborators, Rosemary Dorrington (environmental and molecular microbiology and ecology, RU), Pieter Dorrestein (mass spectrometry and metabolomics of microorganisms, UCSD), and Jason Kwan (metagenomics and microbial natural products biosynthesis) to address the questions of:

1.   Determine whether there are distinct, detectable chemical signaling patterns associated with different microbialite community compositions, as characterized by their morphological and phylogenetic profiles.

2.   Determine which key metabolites are produced by which microorganisms in a microbialite consortium, and explore whether function can be inferred by examining the context of metabolite production.

 


Evolutionary Genomics of Fungal Secondary Metabolism

In collaboration with the research group of Professor Joseph Spatafora (OSU, Botany and Plant Pathology), this project is designed to elucidate evolutionary genetic patterns and processes that operate in the genomic diversification of secondary metabolism in the fungal order Hypocreales, with an emphasis on non-ribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs). Shifts in nutritional mode of these fungi (e.g. leaf/wood endophytes, insect pathogens, mycoparasites) are associated with diversification of secondary metabolism. Knowledge of the phylogeny and evolution of ecologies in hypocrealean fungi may provide a predictive framework for natural product drug discovery.  A current focus is the integration of evolutionary biology with secondary metabolomics and bioassay-guided isolation of selective inhibitors of cellular protein secretion (cotranslational translocation of proteins).  In eukaryotic cells, the majority of secreted and membrane proteins are translocated across or integrated into the ER membrane during their biogenesis at the entrance to the cellular secretory pathway. Loss of proteostasis in the secretory pathway is implicated in major human diseases such as cancer, diabetes and inflammation, and secreted proteins are critical virulence factors for host infection by human pathogenic fungi. Thus, we aim to use natural products from fungi (and cyanobacteria) to probe the feasibility of targeting the Sec61 translocon in human diseases that remain difficult-to-treat, while avoiding toxicities associated with non-selective inhibition of secretory protein biosynthesis.