Cottrell Scholar Awards - 2017
Improving Antibacterial Drug Discovery through Mixed Microbial Culture and Synthetic Organic Chemistry
Each year in the U.S. more than two million people are infected with antibiotic-resistant bacteria and more than 23,000 lose their lives to these infections. Unfortunately, antibiotic development has been in decline since the end of the 1960s due to low profit margins and long research and development times. In 2014-2015 only six new antibacterial agents were approved by the U.S. Food and Drug Administration, but all of these built upon previously known classes of antibiotics for which some bacteria are already resistant.
Amanda L. Wolfe, chemistry, University of North Carolina at Asheville, has received a Cottrell Scholar Award from Research Corporation for Science Advancement to develop a multifaceted approach for rapidly accessing novel and effective antibiotics by first isolating and characterizing new antibacterial compounds produced by mixed microbial cultures of soil bacteria, and then modifying these compounds to improve antibiotic activity against both resistant and non-resistant pathogens.
“Through this work we hope to produce a library of compounds with broad-spectrum activity against many types of bacterial infections,” Wolfe said.
She noted that In the 1990s the first bacterial genome was sequenced, and it was discovered that bacteria possess silent gene clusters capable of producing many novel secondary metabolites with antibiotic activity, many of which have yet to be isolated.
“Today, bacterial secondary metabolites are still an almost endless source of structurally unique natural products with antibacterial activity,” Wolfe said. “The issue is that many of these metabolites are not produced under standard laboratory culture conditions since they are typically synthesized by bacteria for use as signaling molecules or for defense in response to other organisms in their natural environment.”
Her goal is to come up with a method for mimicking the natural environment in which these bacteria live in order to capitalize on this source of potential antibiotics.
To do so, Wolfe and her associates will attempt to develop high-throughput screening methods in which up to 10 varieties of soil bacteria are cultured together and their excreted compounds are tested for antibiotic activity against various pathogens; they will also produce bacterial compounds in large quantities, isolate the potentially active ingredients and characterize their structures using a combination of nuclear magnetic resonance and other advanced techniques. Finally, they hope to rapidly diversify the isolated active molecules and study their structures. If they succeed, they will be able to produce a wide range of potential new drugs.
There is also an education component to the Cottrell Scholar award. Wolfe intends to use some of the funding to improve student learning, retention rates, and the transition into independent undergraduate research projects for chemistry majors at UNC Asheville. She hopes to do this through the development of a junior level Drug Discovery Interdisciplinary Project Laboratory (IPL). It will combine principles of synthetic organic chemistry, computational modeling and biochemistry to design, produce and evaluate novel compounds with medicinally relevant biological activity.