The Ishmael laboratory is focused on drug discovery, with a special interest in compounds that may have potential utility in treating CNS disorders. These studies are part of an ongoing collaboration with OSU colleagues working in the area of medicinal and natural products chemistry. Our present research is focused on identifying the mechanism of action of coibamide A, a novel antiproliferative agent isolated from a Panamanian cyanobacterium by Dr. Kerry McPhail (Pharmaceutical Sciences). We have determined that coibamide induces cell death in human glioblastoma cells via a non-apoptotic mechanism and are using a variety of biochemical, cellular and molecular biological techniques to study the influence of coibamide and other lead structures on the Phosphoinositide 3-kinase / Protein Kinase B / mammalian target of Rapamycin (PI3K/Akt/mTOR) signaling pathway. Our long-term research goal is to identify new biological targets that could be targeted for drug development in the treatment of human disease.
Taifo Mahmud’s research interests span bioorganic and natural product chemistry; biosynthesis of microbial secondary metabolites; and the interface of molecular genetics, enzymology, and chemistry to create and develop novel pharmaceutically active compounds. The group employs a multidisciplinary approach that utilizes cutting-edge technologies in molecular genetics, enzymology, and chemistry to access, study, utilize and manipulate genes and enzymes involved in the biosynthesis of bioactive natural products. Currently, a number of research projects are being pursued in his laboratory. Those include biosynthetic studies and engineered production of bioactive natural products, particularly aminocyclitol- and polyketide- derived compounds, and investigation of bioactive natural products from Indonesian rare actinomycetes.
Structurally complex natural products from diverse biological organisms continue to be a critical source of new chemical entities that serve as lead compounds for drug development and as molecular research probes. Chemical diversity directly correlates with biological diversity, and thus phylogenetically unique organisms from unusual ecosystems are rational sources of new chemotypes with important biological activities. Taking advantage of recent advances in a range of analytical techniques, with an emphasis on nuclear magnetic resonance (NMR) spectroscopy, our laboratory focuses on the discovery and characterization of natural products relevant to cancer and infectious disease research. Three main projects are: Biologically active natural products from deep-sea vent organisms and laboratory-cultured cyanobacteria, synthesis, mechanism of action and in vivo efficacy of the Panamanian cyanobacterial metabolite coibamide A, and South African tunicates as a source of new anticancer agents.
The Philmus lab is interested in the discovery of bioactive natural products that can be used to treat human diseases as well as the biosynthesis and mechanisms of action of these compounds. We approach the discovery of interesting natural products using bioinformatics, genetic, molecular biology and chemical approaches. We have two major projects currently underway. The first is the prediction of gene clusters from sequenced organisms allows chemical structure prediction of the produced natural product and its mechanism of action. We have an active collaboration with the Center for Genome Resources and Biocomputing (CGRB) on campus to undertake this project. The second project involves the creation of a heterologous expression system for the supply of cyanobacterial natural products. Currently, bioactive cyanobacterial compounds can be obtained by collection and isolation of environmental samples or through chemical synthesis. Establishing a heterologous host would allow bioactive compounds to be obtained in an environmentally friendly way. This project involves an active collaboration with Drs. McPhail and Ishmael for identifying and testing our produced compounds.
The main research projects being pursued by Philip Proteau’s laboratory involve various aspects of the chemistry and biology of natural products. All of these projects are collaborative in nature. One project is aimed at the discovery of novel bioactive compounds from Indonesian soil bacteria and a second focuses on the synthesis of the antiproliferative agent coibamide A. These projects incorporate a blend of natural products chemistry, organic synthesis, and spectroscopy.
A key effort is a joint project with Drs. Zabriskie and Mahmud in collaboration with Dr. Dwi Andreas Santosa from the Indonesian Center for Biodiversity and Biotechnology. Dr. Santosa has isolated numerous novel actinomycetes (soil bacteria) from the unique Black Water Ecosystem in Kalimantan, Indonesia and we at OSU culture these bacteria and screen their extracts for biological activity, mainly focusing on antibiotic action. Active extracts are then subjected to fractionation and ultimately isolation and structure elucidation of the active components. Compounds with potential antitumor activity are further explored for mechanism of action by our pharmacology colleague, Dr. Jane Ishmael.
The second project is in collaboration with Dr. McPhail and Dr. Ishmael. Dr. McPhail’s group isolated coibamide A several years ago from a cyanobacterial assemblage collected off the coast of Panama. Inconsistent natural supplies and challenges in culturing the producing organism have necessitated a synthetic route to this highly N-methylated cyclic depsipeptide natural product. In addition to targeting the natural product, we are also working on the synthesis of analogs to address structure-activity relationships. Dr. Ishmael and her students have been studying the molecular mechanism of action of coibamide and also test the synthetic compounds.
Aleksandra E. Sikora’s research is focused on how the extracellular bacterial proteome (cell envelope, surface-localized, and secreted proteins) helps microbes colonize a human or other hosts and environmental niches. The constituents of the extracellular proteome are in close contact with the host tissue and thus represent attractive targets for the development of new therapeutic interventions. She examines these issues using state-of-the-art genetic, molecular, biochemical and proteomic methods, and different animal models (infant and germ-free mouse, Drosophila). During her post-doctoral experience, she has investigated the type II secretion (T2S) pathway that is found in many disease-causing bacteria and is responsible for the delivery of toxins and degradative enzymes to the host organism. In her studies, she has used bacterial pathogens, primarily Vibrio cholerae; the most prominent of a number of Vibrio species that cause the devastating diarrheal disease, cholera. Her work has demonstrated that the T2S system is an attractive target for developing new antimicrobial agents, and accordingly, she has used chemical genomics to identify compounds that interfere with the T2S process. Additionally, by employing high-throughput proteomic approaches she has discovered 16 new proteins that are translocated by the T2S machinery into the extracellular milieu. These proteins represent novel factors that might contribute to V. cholerae pathogenesis and survival in environmental niches. Her laboratory will continue research on V. cholerae and related pathogenic Vibrios, with particular interest in T2S and its secreted effectors. Moreover, she will expand her research program to another human pathogen, Neisseria gonorrhoeae, the etiological cause of the second most commonly reported infectious disease in the United States. Gonoccocal infections are often asymptomatic and in women can have devastating sequelae: pelvic inflammatory disease, ectopic pregnancy and infertility. With no effective vaccine and only a single class of antimicrobial agent currently available to treat gonoccocal infections, gonorrhoea represents a public health crisis. The Sikora lab efforts will focus on identification and elucidating novel components in N. gonorrhorhea extracellular proteome as potential targets for antimicrobials and vaccine candidates.
Research in the Stevens laboratory is aimed at determining the role and function of vitamins and dietary phytochemicals in human health and disease. Dr. Stevens’ research is closely aligned with the research mission of the Linus Pauling Institute at OSU (http://lpi.oregonstate.edu/). Mass spectrometry-based metabolomics is a new direction in the Stevens laboratory for a discovery of biological effects and mechanisms of actions.
Project 1: Xanthohumol and metabolic syndrome Dr. Stevens and his associates have discovered that the hop natural product, xanthohumol, exerts anti-obesity and anti-hyperglycemic effects in animal models of metabolic syndrome. Current research on xanthohumol, now marketed as a dietary supplement and food additive, is focused on its fate in the human body and its effects on gene regulation relevant to lipid and glucose metabolism. Xanthohumol could earn a place in the early treatment of metabolic syndrome to prevent or retard the development of atherosclerosis and diabetes (Funding: NIH/NCCIH and Hopsteiner, Inc.).
Project 2: Vitamin C mitigates cardiovascular disease Cardiovascular disease finds its origin in a chronic inflammatory state of the vasculature. Dr. Stevens and other investigators of the Linus Pauling Institute have shown that vitamin C supplementation reduces the formation of pro-inflammatory lipid peroxidation products in humans, which is significant because many large clinical trials have not been able to establish any effect of vitamin C on biomarkers of oxidative stress. The Stevens lab is also investigating the beneficial effects of vitamin C in the prevention of tolerance against nitrate therapy.
Other projects: 3) Brain stimulants from the medicinal herb, Centella Asiatica, in the fight against Alzheimer’s disease (Funding: NIH/NCCIH), and 4) Bioactives from the oilseed crop, Meadowfoam (Limnanthes alba) (Funding: Natural Plant Products, Inc.).