A profile on two BTI researchers looking into solutions for antibiotics and anti-cancer therapies
Katie Sabbia (writer), Mikaela Armstrong (photographer)
UMN scientists extract high-value beta-lactones from waste for use in antibiotic and anti-cancer therapies.
From biofuels to antibiotics
Sustainability. It’s more than a buzzword. Recycling is a key component in a circular economy, where consumer and industrial waste become raw materials instead of landfill. University of Minnesota biochemist Larry Wackett sees high-value beta-lactones as ideal targets in a new circular economy. His laboratory works with genetically engineered strains of E. coli that convert fatty acids into beta-lactones– a key component of industrial products from pesticides to antibiotics and anti-cancer agents. Chemical synthesis of beta-lactones is painstaking and costly with yields as low as 1%. The Wackett lab’s technology could provide a reliable and efficient pipeline at a fraction of the cost.
An expert in biocatalysis, Wackett uses enzymes to transform organic compounds, whether breaking down environmental toxins or synthesizing chemicals for agriculture and industry. While working on a Department of Energy grant to develop ethanol substitutes, his lab inserted genes from soil bacteria into E. coli. They planned to synthesize fatty acids as a precursor to hydrocarbon fuel production, but instead, James Christenson, then a graduate student in the Wackett lab, made a crucial discovery. While analyzing precursor molecules in hydrocarbon biosynthesis, he identified one intermediate molecule as a beta-lactone.
Christenson, who went on to earn his doctoral degree in Wackett’s lab, carefully isolated and identified the enzymes and other components of the chemical reactions and repeated the steps in vitro. Scientists already knew that some bacteria produced beta-lactones, but Christenson’s work revealed the biochemical mechanism by which they are created. For the first time, the beta-lactones could be made biologically by a directed process. Christenson presented his discovery at the Enzyme Mechanisms Conference in 2017 where he was sole recipient of the Founder’s Award in a competitive field of world class researchers.
“We have published a lot of papers on how to make hydrocarbons, so we did the work we set out to do,” Wackett explains. “But in the process, we discovered something else. Beta-lactones are highly valued as anti-cancer, anti-obesity, and antibiotic agents. As antibiotic resistance increases, this may be even more important than the biofuels project.”
Beta-lactones are similar in structure to the key components of antibiotics like penicillin that work by inhibiting cell wall production in the targeted bacteria. Antibiotic-resistant bacteria have evolved to resist these molecules, and rendering them ineffective. In the war on antibiotic resistance, beta-lactones could be our next line of defense.
Small molecule, big impact
“We can purify enzymes at very high yields, and we can make a lot of different structures with different properties.” To understand the structure of these complex enzymes and how they interact with other molecules, he turned to longtime collaborator Carrie Wilmot. Wilmot, an X-ray crystallographer and professor in the Department of Biochemistry, Molecular Biology, and Biophysics, helped identify the structures and mechanisms of the proteins producing the beta-lactones. Her lab produced three-dimensional models of the molecules using the diffraction patterns derived from exposing protein crystals to high energy X-rays. Viewing such models on a computer will help the team find and engineer the best enzymes to synthesize new and useful beta-lactones.
Wackett is committed to seeing his research applied outside the academic laboratory. He and his co-workers filed a patent for the process which can be used to make beta-lactones with different properties and ideally, some will be useful as drugs to treat cancer or bacterial infections.
With a seed grant from the MnDRIVE Environment Initiative, Wackett is partnering with Minnesota-based life science firm Bio-Techne to look at commercial processes for producing beta-lactones. The ultimate goal is to develop a key component of the circular economy: converting wastes to high value products.