A Team Science Publication Resulting from the College’s Kentucky Coal Mine Research is the College’s Monthly Highlight

July 19, 2015

A natural product discovery from a Kentucky coal mine fire site that shows promise in battling alcohol dependence is the UK College of Pharmacy Research Publication Highlight for June 2015.

The article was published in Organic Letters and is entitled, “Terfestatins B and C, New p-Terphenyl Glycosides Produced by Streptomyces sp. RM-5-8.”

This team science project was orchestrated by Jon Thorson, Professor in the Pharmaceutical Sciences Department and Director of the Center for Pharmaceutical Research and Innovation, in collaboration with Mark Prendergast, Professor in the Department of Psychology, Steven Van Lanen, Associate Professor in the Pharmaceutical Sciences Department, Andrew Morris, Professor in UK’s Division of Cardiovascular Medicine, and Dr. James Hower, a research scientist at the University of Kentucky Center for Applied Energy Research and adjunct professor in the Department of Earth & and Environmental Sciences. The first author was Xiachang Wang, a Postdoctoral Fellow in the Thorson Laboratory. Also contributing were postdoctoral researchers Sherif Elshahawi and Yinan Zhang, as well as graduate students, Anna Reynolds and Meredith Saunders and undergraduate student Ibrahim Elgumati. Staff working on the project included Larissa Ponomareva, Khaled Shaaban, Manjula Sunkara and CAER Eastern Kentucky Program Coordinator Gregory Copley.

Continuing the ongoing efforts focused on the discovery of new natural products from untapped environments throughout the Commonwealth, the current study highlights the discovery of two new p-terphenyl glycosides (terfestatins B and C) from a Streptomyces strain associated with thermal vents emanating from the Ruth Mullins underground coal mine fire in Perry County, Kentucky. An unusual feature of these metabolites was an attached rare sugar (the unsaturated hexuronic acid 4-deoxy-α-L-threo-hex-4-enopyranuronate) also found appended through a distinctive glycosyl connection to a second distinct metabolite class (5-isoprenylindole-3-carboxylate) isolated from the same strain. In addition, as part of the CCTS Team Science Pilot program focused on the discovery of new agents to treat nicotine and alcohol abuse (led by Kim Nixon, Associate Professor of Pharmaceutical Sciences with participating investigators including Mark Prendergast and Michael Bardo, Professors in the Department of Psychology and Linda Dwoskin, Professor of Pharmaceutical Sciences), terfestatin B was demonstrated to display potent and specific functional cytoprotection against alcohol-induced toxicity (neuronal and glial degeneration) in a primary rat brain cell culture model. This work adds to the collection of novel bacterial natural products deriving from the Commonwealth, highlights Streptomyces sp. RM-5−8 as a source for a potentially permissive enzyme catalyst (a glycosyltransferase), and uncovers a new therapeutically relevant activity of the terfestatins. Work is underway to understand the molecular neuroprotective mechanism(s) of action and assess the potential in vivo efficacy of these unique natural products.

“This research establishes the p-terphenyl scaffold as a new natural product-based pharmacophore with exciting translational potential that may address the neurodegenerative sequelae of alcohol dependence,” said Linda Dwoskin, Associate Dean for Research.