Forestalling pesticide, antibiotic resistance possible, theory predicts

August 21, 2001

WEST LAFAYETTE, Ind. -- For years, farmers and agribusinesses have talked about being on the "pesticide treadmill": A few years after a pesticide is introduced, insects develop resistance to it. So another chemical is used -- at least until the bugs overwhelm that one.

Then another chemical is used. Then another. Then another.

But Barry Pittendrigh, assistant professor of entomology at Purdue University, says it's possible to stop the treadmill, or at least slow it to a crawl.

Pittendrigh and Patrick Gaffney, of the University of Wisconsin-Madison, have developed a method to use pesticides so that genetic resistance doesn't arise.

The technique is called negative cross-resistance, and it involves using multiple pesticides in a precise way to stop the pests.

With the technique, scientists would identify a second biocide -- pesticide, antibiotic, herbicide or fungicide -- that specifically kills the resistant pest. Then the two biocides would be used together, either concurrently or alternated, to prevent resistance.

Previous attempts to find compounds that would have a negative cross-resistance effect haven't worked because they focused on fewer than several dozen compounds, Pittendrigh says.

However, Pittendrigh says it is necessary to screen upwards of 100,000 compounds to develop a negative cross-resistance system. Pittendrigh and Gaffney have invented a method to conduct these screens.

"Specifically, in our paper, we outline how companies or individuals can search for and develop NCR compounds to a commercially applicable level," Pittendrigh says. "This paper provides part of the theoretical framework for research currently in progress here at Purdue for the development of negative cross-resistant toxins and their use in field applications."

The researchers say their model shows that using negative cross-resistant biocides could delay resistance for decades, or even more than 100 years in some situations.

"Although negative cross-resistance is not 'the' answer to dealing with resistance to pesticides, it certainly has the potential to play a significant role in dramatically slowing the rate at which resistance enters insect populations," Pittendrigh says.

The result, the researchers say, would be reduced costs, both financial and social.

"Nature will always find a way to get around whatever we do to control organisms," Pittendrigh says. "But in some cases, this method may buy us years of usefulness for compounds that are on the market. It costs a large amount of money to bring a pesticide to market. If it's a highly important biocide, such as an insecticide for a major pest or an important antibiotic, this method could have great value."

The method is described in a paper appearing Tuesday (8/21) in the Journal of Theoretical Biology. The research was funded by the Purdue Department of Entomology.

Pittendrigh says, in theory, the method also should work to prevent antibiotic resistance in bacteria.

"Although this paper is primarily focused on issues of insecticide resistance, we don't rule out the possibility that this approach may also be useful in combating antibiotic resistance," he says. "But, we will leave the applicability of NCR in bacteria to those that work in antibiotic resistance."

The method also could be used with herbicides or fungicides.

No pesticide is 100 percent effective against its target, and that's where the problem of chemical resistance comes in.

If a pesticide kills 98 out of 100 bugs, the only two left are both resistant to the chemical. If those two mate, then all of their offspring also will be resistant.

If the same thing happens in field after field, soon entire populations of the pest are immune to the effects of the pesticide.

The situation is worse with genetically modified crops, such as Bt corn. Because these plants deliver pesticide in such a direct and effective manner, they are even more susceptible to the rise of resistant insects.

Although resistance can vary, some examples of insect resistance can be dramatic.

Dieldrin is a compound no longer used commercially, but still commonly used in laboratories. Scientists often use fruit flies, called Drosophila, in their experiments, and certain strains of Drosophila are so immune to Dieldrin that they can walk unharmed on pure crystals of the pesticide.

Scientists are able to create resistant insects in the laboratory by using a process known as EMS (ethylmethylsulfanate) mutagenesis. Using the compound, scientists can produce insects with great genetic variability, and screen for those that are resistant to the insecticide being tested.

"With EMS mutagenesis you can actually create resistance in the laboratory that is similar to that in the field," Pittendrigh says. "As a general rule, this mimics nature, but at a much faster rate."

Once a new compound has been identified as being effective on resistant pests, it can either be alternated with the original biocide, or they can be paired together.

"My own bias is to use two compounds at once, because, at the end of the day, it's the simplest method," Pittendrigh says. "Farmers could spray with the original pesticide for five years, and then in the sixth year everybody would have to use both pesticides. But if somebody tried to cut corners and didn't use both compounds, the method wouldn't work. That's why my bias is to use two compounds concurrently because it's the easiest to manage."

Although using two pesticides is obviously more expensive than using just one, Pittendrigh says genetically modified crops lower this hurdle.

"With traditional agriculture, there are concerns about the costs of delivering two different pesticides at once," Pittendrigh says. "But with genetically modified crops, it's much easier and much more cost effective to deliver two pesticides."
Pesticide resistance: Can we make it a renewable resource?
B.R. Pittendrigh, Dept. of Entomology, Purdue University, West Lafayette, Ind.;
P.J. Gaffney, Dept. of Statistics, University of Wisconsin, Madison, Wis.

Negative cross resistance (NCR) occurs when a mutant allele confers (i) resistance to one toxic chemical and (ii) hyper-susceptibility to another. Sequential deployment of NCR toxins is useful for insect control in a few situations (Pittendrigh et al, 2000). Using Monte Carlo simulations, we investigated the concurrent use of a pair of NCR toxins to control a hypothetical insect pest population. When the toxins killed more heterozygotoes than homozygotes, the resistance allele became either extremely common or rare depending on starting allelic frequency. If the NCR toxins did not kill the two homozygous groups equally, then the toxin with lesser toxicity eventually played a greater role in the control of the pest population. Based on our results, we present an approach for the systematic development of an NCR toxin after the commercial release of the first toxin. First, large-scale screens are performed to find the chemicals that kill the resistant homozygous insects, but not the susceptible ones. Chemicals that preferentially kill resistant insects are then tested for toxicity to the heterozygotes. Those highly toxic to both homo- and heterozygotes are given the highest priority for development. This screen can be adapted to identify compounds useful in controlling antibiotic-, herbicide- or fungicide resistant organisms.

NOTE TO JOURNALISTS: For additional background, see Pittendrigh, B., Gaffney, P., and Murdock L. 2000. "Deterministic modeling of negative cross-resistance for use in transgenic host-plant resistance," Journal of Theoretical Biology, 204:135-150.

Source: Barry Pittendrigh, 765-494-7730;

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