A biotech insect repellent, safe enough to eat

The fledgling metabolic engineering industry expands its products to pest control.

A compound originally from grapefruit skin, now made using genetically engineered yeast, can be used as an insect repellent or insecticide, according to a decision from the US Environmental Protection Agency (EPA) in August. The approval of the compound, nootkatone, for pest control strengthens the footing of the fledgling metabolic engineering industry, whereby companies use fermentation methods to manufacture prized plant-derived biomolecules. Evolva, based in Reinach, Switzerland, developed the ingredient through a collaboration with the US Centers for Disease Control and Prevention (CDC).

Nootkatone’s fragrance is pleasant to humans but not to insects. The sesquiterpenoid, which is found in grapefruits, now has a green light for use as an insect repellent. Elizaveta Galitckaia / Alamy Stock Photo.

Nootkatone marks this industry’s first foray into pest control. But it is not the first microbe-derived biomolecule on the market: several others are already being sold. The short list includes vanillin, a compound carrying the characteristic flavor of vanilla; resveratrol, sold as a health supplement; key molecules found in the sweetener stevia; and valencene, which can be used as a citrus flavor and fragrance ingredient (Table 1).

Table 1 Selected ingredients derived from fermented microbes

In nature, nootkatone is present in minute quantities in the skin of grapefruit and in Alaska yellow cedar trees. It carries the characteristic smell and taste of grapefruit, and the flavor and fragrance industries use the extract in products such as sodas and perfumes. In larger quantities, nootkatone repels ticks, mosquitoes and other biting insects on par with DEET (diethyltoluamide) and other bug sprays on the market.

It takes about 400,000 grapefruits to make 1 kg of nootkatone, according to Evolva. A liter of highly purified food-grade nootkatone can cost up to $4,000. That price point may work in the flavor industry, where small amounts suffice. But larger amounts are required for bug repellents and insecticides, so sourcing nootkatone from fruit or trees isn’t economically viable.

Nootkatone can be synthesized chemically, but the process is tricky and inefficient. “It usually takes a lot of steps to synthesize with pure chemistry, so at every step you lose some portion of the starting material,” says Karla Addesso, an associate professor in the department of agricultural and environmental sciences at Tennessee State University. “You might get 50% of the final nootkatone product with the most efficient protocols, and so you have to throw out 50% of what you made.”

Coaxing yeast to produce nootkatone precursors, however, is a viable and cost-effective alternative. Researchers turn these organisms into little biofactories by modifying their genome to produce key enzymes to manipulate metabolic pathways involved in producing intermediates to nootkatone. The engineered microbes are then grown via a fermentation process using sugar as a feedstock (Nat. Biotechnol. 33, 329–332, 2015).

Evolva accomplished nootkatone production via a semisynthetic process by adding a single gene from thistle to the yeast species Saccharomyces cerevisiae. The engineered yeast produces valencene, a chemical intermediate to nootkatone. Valencene is then subjected to chemical oxidation and purification steps, yielding over 99% pure nootkatone with a chemical structure identical to that of the extract, according to Evolva. Because Evolva uses a chemical conversion step and catalysts, the company’s nootkatone compound cannot be marketed to US consumers as a ‘natural’ ingredient.

Even so, the fact that nootkatone is found natively in food may make it more appealing to consumers who are looking for an alternative to DEET and other common, chemically synthesized bug spray ingredients. “It smells nicer and it works just as well, and because it’s a food additive you can eat it,” says Addesso. “I feel like it’s going to have a slightly more favorable adoption for people who are concerned about using DEET, whether they feel it’s not safe or they don’t like the smell,” she says. Nootkatone’s mode of action, while not fully understood, may be different from that of DEET and other pest control ingredients. That would make it ideal in geographical regions where insects are developing resistance to common insecticides.

Evolva will market the ingredient under the name “NootkaShield” and will partner with companies large and small to incorporate it into product formulations. Each of these formulations will require a separate EPA registration. “Some of the formulations we’d love to see down the road are things such as a lotion repellent that can be sprayed on clothes or rubbed onto the skin in the morning and it would stay there through the day and repel ticks” and other insects, says Ben Beard, deputy director of the division of vector-borne diseases at the CDC. “Or a soft soap or a shampoo that could actually kill ticks would be very helpful.”

Oliver Walker, CEO of Evolva, says that in addition to the use of nootkatone on people, he sees a market for it as a protectant for cattle against bovine ticks. Nootkatone as an insecticide for crops and other agricultural applications “is probably a long shot,” he says. “All those chemicals are dirt cheap.”

The initial discovery and patents for nootkatone from microbes arose from the work of the CDC. The agency in 2014 licensed the technology to Allylix, which was acquired by Evolva the same year. Two years later, the CDC and Evolva established a research agreement to conduct safety and efficacy trials using nootkatone as a repellent and pesticide against ticks and mosquitoes. In 2017, after the Zika virus outbreak, Evolva received $8.35 million through a contract with the CDC’s sister agency, the Biomedical Advanced Research and Development Authority (BARDA), to advance the development of nootkatone for the protection against mosquito-borne diseases.

At least two other companies — Isobionics in Geleen, the Netherlands, and Oxford Biotrans in Milton Park, UK — have been working on the production of nootkatone from the fermentation of microbes. Both companies have thus far targeted the flavor and fragrance industries. State-sponsored Chinese researchers have also genetically modified yeast to produce nootkatone.

“If we can find other plant compounds that are really effective that can be created cheaply this way, it might open the door for new biofriendly, environmentally friendly insecticides and repellents,” says Addesso. “The trajectory in the pesticide world has been to make things safer. If you can make things like this that [people] can eat and is also effective, you want to move in that direction.”

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Waltz, E. A biotech insect repellent, safe enough to eat. Nat Biotechnol 38, 1368–1369 (2020). https://doi.org/10.1038/s41587-020-00760-z

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