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Bug patrol.

Chemical resistance has helped turn insects like spider mites and bed bugs into ubiquitous and voracious pests. can natural products chemistry help halt these blighters in their tiny tracks?


Vancouver has an itch that just won't go away. Luckily, Darin Craig, a service manager with Local Pest Control, has swooped in to scratch it. "I've treated this unit in the past," Craig says, helping Michael, a resident in a downtown Vancouver multiunit social housing complex, pull the mattress upright to check for evidence of infestation. "I had three bites on my leg," Michael complains. "When I'm in my bed I'm scratching."

Working together, the men pull layer after layer of sheets and pads off the mattress. "I like my comfort," Michael confesses sheepishly. Craig detects no signs of unwanted bed bug (Cimex lectularius) roommates--no telltale bloodstains or tiny dark spots of fecal matter. Nonetheless, Craig isn't taking any chances. It's only been a month since his last visit to this building to spray other suites, so he opts for a two-pronged attack using a residual as well as non-residual insecticide. (A non-residual insecticide dissipates within a short period of time and is considered nontoxic to humans; a residual spray remains effective for much longer but can cause a reaction.) Craig sprays the sheets and mattress with the non-residual Better Than Bed Bug Killer, which contains the active ingredient d-Phenothrin. The insecticide belongs to the pyrethroid family, a synthetic version of pyrethrins, which are natural insecticides derived from chrysanthemum flowers. For longer-lasting effect, Craig uses the residual insecticide Tempo WP containing Cyfluthrin, another synthetic pyrethroid that is toxic not only to insects but other invertebrates. (Pyrethrins act as an axionic excitotoxin on bed bugs, which effectively paralyzes them by messing with the sodium channels that regulate their nerve cells.) Craig shoos Michael out of his suite for a minimum of four hours to ensure he isn't affected by the application of Cyfluthrin, then pulls on his purple respirator and closes the door to begin spraying every nook and cranny of the room.

After five minutes, Craig comes back into the hallway and pulls his respirator off. His job, he says, is becoming more of a challenge. Generally, conventional insecticides like DDT, lindane and dieldrin, which are restricted persistent organic pollutants, have become less effective against bed bugs. In the six years since Craig has been on the frontlines of bed bug patrol in Vancouver, the number of complaints has skyrocketed. Once isolated to the flophouses of Vancouver's poverty-stricken Downtown Eastside, there is now no "class differentiation," says Craig, whose pyrethroid cocktail seems to be keeping the bed bugs (just barely) in check at this building. On a global scale, however, bed bugs have the upper hand. "Bed bugs are found everywhere," Craig says.

Humans and bed bugs--flat, brown and the size of a lentil--have lived in uneasy symbiosis for millennia. It is theorized that bed bugs latched on to humans in prehistoric times, coming along for the ride as humans' home-hunting efforts evolved from caves to tents and, finally, houses. Following the Second World War, chemistry came to the rescue, and broad-spectrum synthetic insecticides, including DDT, proved effective in controlling bed bug populations. However, the critters rallied at the turn of the 21st century, thanks in part to an increase in global air travel. The 2000 Sydney Summer Olympics in Australia appeared to be the tipping point. By the end of the 16-day event, virtually all of Sydney's hotels had at least one infected room. Slow reactions on the part of hoteliers meant the bugs quickly spread, hitchhiking their way to North America and Europe in athletes' and spectators' suitcases. Infestations--especially in hotels--have been on the rise ever since.


It was a debate with a friend over whether the 2010 Winter Olympics in Vancouver would generate the same bed bug plague that led Karn Manhas, the founder and CEO of the biotechnology company Terramera Inc., to set up a laboratory in his basement to try to concoct a bed bug brew that would blast the blighters once and for all. At the time, Manhas was a law student at the University of British Columbia, although he had studied genetics and biotechnology at McGill University as an undergrad. Manhas' family was involved in Vancouver real estate and the expected influx of people from abroad had them worried that there would he a repeat of the Sydney infestation. Manhas was aware that bed bugs had developed resistance to such tried-and-true insect killers as deltamethrin, another pyrethroid derivative found in the popular insecticide Raid. "In the United States, it's estimated that from 70 percent to 90 percent of all bed bug strains have resistance," says Manhas, dressed in jacket and jeans, seated at a round table in Terramera's laboratory facilities, located in a quiet business area of Vancouver.

Could anything thwart these pests? Manhas felt that the answer might lie in the traditions of his family's homeland of India. Manhas' parents had immigrated to Canada from the South Asia nation and, as a child, his parents would visit India, returning with small bags of neem bark for the kids to chew on after meals. "You can imagine how cool it was to brush your teeth with bark," Manhas says. The neem tree (Azadirachta indica) is an integral part of the ancient system of Ayurveda preventive medicine. Over millions of years, plants and animals, on land or at sea, developed chemical defences to protect themselves from pests. The neem tree is no different, and one of its active compounds is azadirachtin, found in the oil of its seeds. Neem has been in use for the past 5,000 years and is still utilized today as a pesticide as well as a medication against lice infestations and as a treatment for acne and eczema. It is also found in cosmetics. Neem leaves also contain the compounds gedunin and nimbidol, which kill fungi. The leaves of the tree, says Terramera's Chief Science Officer (CSO), chemist Annett Rozek, have traditionally been stored with grains--beetles and weevils can't tolerate neem leaf volatiles.

The challenge facing Manhas, who eventually moved his basement laboratory to its current location, was identifying, isolating, extracting and enhancing the active ingredients in neem oil. Although azadirachtin has been identified as the key active ingredient in neem, its synthesis, which would have allowed widespread commercialization, had eluded chemists for 40 years. (It was finally synthesized in 2007 by United Kingdom researchers.) However, the synthesis isn't perfect, says Rozek, due to the complexity of the azadirachtin molecule. It contains 16 stereocentres in the molecule, or carbon atoms to which different chemical groups or hydrogens can be attached in mirror image arrangements. Of these, says Rozek, seven are tetrasubstituted, which means they have four substituent groups attached to the same carbon atom. "That's the complication in the synthesis, the seven are adjacent." This complexity makes it hard to synthesize a molecule that is exactly the same as the natural one, Rozek says.


Typically, natural pesticides don't work as well as synthetic ones. Neem, indeed, can be capricious, its efficacy compromised by its sensitivity to light, Rozek says. Therefore, the challenge for Terramera wasn't extracting the oil from the neem seeds. (The company uses the same cold press system used to extract olive oil from olives). Rather, it was creating a formulation that would enhance the bioavailability of the oil's more than 150 compounds (including azadirachtin), thus turning it into a commercially viable product that would be consistently efficacious and have a long shelf life. This formulation--proprietary and patent-pending--is called inSpirium. It enhances the availability of all neem oil's bioactive compounds in addition to azadirachtin, says Manhas, who won't detail how inSpirium works. However, the results to date are stellar. Terramera's flagship biopesticides, Proof and CIRKIL, which differ only in the amounts of azadirachtin present, kill adult bed bugs as well as the eggs. Recently licensed in the United States, both of these products claim to be 100 percent effective against bed bugs and have been tested by Good Laboratory Practice (GLP) standards. (Terramera has applied to register the products for use in Canada.) Proof and CIRKIL underwent extensive testing in Terramera's labs and, while sharply pungent, both are benign to humans, even when sprayed in close quarters. (Terramera keeps a bevy of bed bugs for research, keeping them healthy and happy on human blood donated by staffers.)

Rozek believes that part of azadirachitin's efficacy--in addition to the inSpirium formulation--is derived in large part from working in concert with the 150-plus compounds found in neem oil. This complexity means there is less likelihood that a pest will develop resistance down the road, adds Rozek, noting that Terramera is isolating and testing these other neem compounds to identify their unique properties.

Terramera's research arm has extended into agriculture, Manhas says. In cooperation with numerous universities in the US, Terramera has launched studies into nematode control. Nematodes (Nematoda) are parasites that attack the roots of valuable crops like tomatoes, cotton, peanuts, corn and soybeans as well as greenhouse plants. Increasing resistance to conventional pesticides, in addition to the banning in 2010 of the popular product aldicarb (a neurotoxin that is also poisonous to humans) means that farmers are on the hunt for alternatives. Recent studies comparing neem-based applications to conventional ones indicate that Terramera's products are as equally effective or more so than commercial pesticides, Manhas says. Another problem where Terramera's neem products are proving effective is against the fungi Fusarium oxysporum, Botrytis cinerea and Erysiphe nectator, also known as powdery mildew. Botrytis and powdery mildew afflict major crops like California grapes. The resulting fungal rot causes about $750 billion in damage worldwide, says Manhas. Fungal pathogens like powdery mildew are yet another scourge becoming chemically resistant. "Our products have the potential to create huge amounts of change along the entire food chain," he says.


Natural products to thwart agricultural pests are also being developed in the laboratories of Vojislava Grbic and Miodrag Grbic of Western University's Department of Biology. Co-researchers who are also married, the couple is focused on developing sustainable and environmentally friendly approaches to control the two-spotted spider mite (Chelicerata), a voracious arthropod only 0.3 millimetres long that enjoys a vast buffet of 1,100 plant species, 150 of which are major agricultural crops. (Spider mites have a stylet that they use to suck out the contents of plant cells, causing the leaves to yellow and affecting photosynthesis.) To date, these creatures have been controlled using pesticides like Etoxazole that prevents them from growing chitin, the hard substance needed to grow a protective exoskeleton. However, spider mites are showing resistance to a variety of pesticides, due in part to a remarkable "set of detoxification genes," says Miodrag, who heads an international consortium called the Genomics in Agricultural Pest Management, or GAP-M, a global collaboration that includes Genome Canada as well as science specialists around the world.

There is one item on the spider mite buffet, however, that is its downfall. When mites chow down on members of the Brassicaceae family, which includes thale cress (Arabidopsis thaliana), the plant switches on genes that produce molecules called indole glucosinolates. Also found in plants like cabbage and broccoli, glucosinolates, while benign to humans, increase mite mortality rates, Vojislava says. (A Saskatchewan company, MPT Mustard Products, is developing a biopesticide containing glucosinolates that are derived from mustard seeds for this very purpose.) "This is just the tip of the iceberg," says Miodrag. "These indole glucosinolates are one of the first plant-based metabolites that could be effective against spider mites. Our research should identify many more plant-producing metabolites that can be used to control mites."

Complementing the Grbic's biopesticide studies is research into double-stranded RNA, or small interfering RNA (siRNA), which is involved in a process called RNA interference (RNAi). This is being investigated as a means to turn off targeted genes in the spider mites. RNAi has the potential to silence spider mite genes that are essential for their survival, says Vojislava. The Grbics are also investigating a way in which to "vaccinate" plants to make them capable of defending themselves against spider mites. "It's providing a totally new toolbox," Miodrag says.

The world is looking for more ecologically acceptable and environmentally safe products--especially as the planet's raft of insects and pests build resistance to tried-and-true chemical solutions, threatening the food crops that are needed to feed an ever-growing population. The development of natural products chemistry --investigating Mother Nature's solutions to pest control--is proving to be an ever-increasing and important area of research into this age-old battle between man and tiny beast.

Caption: Pest controller Darin Craig is on the frontlines Of Vancouver's bed bug problem.

Caption: The bed bug has become increasingly resistant to conventional pesticides.

Caption: The complexity of the azadiracthin molecule has been an obstacle to its synthesis.

Caption: As a pest-control expert, Darin Craig's arsenal of pyrethroid-based sprays is barely keeping bed bugs in check.
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Title Annotation:Chemistry: Natural Products
Author:Staley, Roberta
Publication:Canadian Chemical News
Geographic Code:1CANA
Date:Jan 1, 2015
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