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Negative Cross Resistance (NCR)

This site is maintained by the Pittendrigh and Gassmann Laboratories.


Definition of NCR: Negative cross-resistance (NCR) occurs when a novel allele confers (i) resistance to one toxic chemical or environmental factor and (ii) hyper-susceptibility to another. That is to say, a trade-off occurs in which the benefit of resistance to one factor arising at the cost of greater susceptibility to a second factor.

Video created by Emre Erin. Erratums to the video include: (1) in scene #3 "Achilles heel" should be "Achilles' heel" and (2) in scene #6 "...the resistant allele." should be "...the resistance alleles."

Two of the more important scientific events of the 20th century have been the green revolution and the development of antibiotics. The green revolution, with the large-scale use of insecticides and herbicides, has increased the quantity and quality of food for an ever-growing human population.  In addition, antibiotics have dramatically reduced the mortality rates, in the human population, that occur as a result of bacterial diseases.  However, the Achilles' heel of both  scientific advances has been the evolution of resistance.

Although efforts have been made to slow down the development of resistance to pesticides and antibiotics, if these compounds are used improperly the evolution of resistance is inevitable. Once widespread resistance develops, the chemical (or chemical class) is typically abandoned. The subsequent focus in the academic and industrial research community is on identifying and deploying novel pesticides and antibiotics with different modes of action. One alternative to this “use-and-discard'' approach exploits negative cross-resistance (NCR) strategies to from a population those organisms that contain resistant allele (Pittendrigh et al., 2000).

Although NCR occurs across a wide array of toxins and organisms, including insects (Peiris and Hemingway, 1990; Hemingway et al., 1993), weeds (Oettmeier et al., 1991) and fungi (Josepovits et al., 1992), it has rarely been used commercially (Yamamoto et al., 1993; Hoy, 1998). Additionally, the concept of negative cross-resistance is not a new one, with examples dating back to the early 1960s (Ogita, 1961 a, b, c). Why are there so few commercial examples of NCR?

Pittendrigh and Gaffney, 2001

Perceived Limitations of NCR

Five perceived limitations of negative cross-resistance have likely played a significant role in preventing people from investigating NCR as a practical control strategy. We have tested these five perceived limitations and demonstrated that these assumptions are incorrect. Thus, NCR factors have the potential to be useful in insect control.

(1)  NCR factors will be hard or impossible to identify in screens.

We tested this hypothesis using a DDT-resistant strain of Drosophila melanogaster, with a known resistance mutation in the para gene.

Conclusion – We observed a NCR factor while screening fewer than a dozen compounds (Pedra et al., 2004). Thus, NCR factors are not difficult to observe.

(2) NCR factors cannot effectively alter the frequency of resistance alleles in an insect population.

We again tested this hypothesis using a DDT-resistant strain of D. melanogaster, with a known resistance mutation in the para gene, and demonstrated that at least in laboratory experiments NCR compounds could shift allelic frequencies of the resistance genes (Pedra et al., 2004).

Conclusion – NCR factors can be used to alter allelic frequency of resistance alleles.

(3)  Only highly toxic NCR compounds can be used to minimize resistance in an insect population.

We tested this hypothesis in collaboration with Drs. Onstad, Murdock, Roush and Huesing, using computational modeling of the concept of an “active refuge” strategy (Pittendrigh et al., 2004).  Dr. Aaron Gassmann and collaborators (Gassmann et al.,  2008, 2009) independently tested this concept and came to the same conclusions.

Conclusion – One extremely exciting finding that emerged from this work is that even compounds (or ecological factors) that are moderately toxic to the resistant insects can be used to minimize resistance in the insect population.  The “active refuge” approach is analogous to an oil filter in an engine of a car, where the NCR compounds (or ecological factors) actively “filter” the resistance alleles out of the insect population.

(4)  There are no effective screening strategies for NCR compounds.

We have proposed, and in some cases developed, screening strategies for the effective discovery of NCR compounds (Pittendrigh and Gaffney 2001; Pittendrigh et al., 2008; Pittendrigh et al., unpublished).

To discover NCR factors, companies need to incorporate the same large-scale screening effort which they now use to discover insecticides with new modes of action. We do not rule out the possibility that NCR screens may have been tried by companies, in the past, with few successes due to the limitations of the technologies and the lack of understanding of biological systems impacted by the toxins. But, with the advent of clonable polypeptide pesticides, and directed mutagenesis, coupled with a greater understanding of the nature of the target systems, the discovery of NCR toxins may become more feasible. Negative cross-resistance screens will involve identifying toxins that selectively kill insects resistant to commercially deployed insecticides. The development of NCR screens will require the knowledge of parameters important for the discovery of new compounds that provide NCR to existing pesticides.

Pittendrigh and Gaffney, 2001

Conclusion – There are effective ways in which NCR compounds can be screened for using resistant insects or other in vitro/vivo systems.

(5)  There are no effective deployment strategies for the use of NCR compounds.

We tested this hypothesis through computational models to determine potentially effective approaches for deploying NCR compounds or agents.

Conclusion – We observed that the “active refuge” strategy for deploying NCR compounds was a potentially effective approach.

View the Video Assisted Scientific Article on this topic: In English | En Español

“Ecological Negative Cross-Resistance (eNCR)”

Although much of our previous work has focused on the concepts of screening for and developing commercially viable strategies for negative cross-resistance compounds, arguably the most exciting approach for practical application of this strategy involves “ecological negative-cross resistance” (eNCR) (Pittendrigh et al., 2008). Ecological negative-cross resistance factors are biological agents that cause greater mortality in pesticide-resistant versus pesticide-susceptible insects.  Such eNCR agents may include host plants, predators, parasites, bacteria, and viruses.

Additionally, eNCR can occur in plants that are resistance to herbicides.  For example, certain herbivorous insects are known to magnify the fitness costs of resistance in the pigweed (Amaranthus hybrids) to the the herbicide triazine.

“Broad spectrum NCR compounds”

Recent work by Nguyen et al. (2007) suggests that broad spectrum NCR compounds exist and can possibly be used against resistant insects with highly divergent resistance mechanisms.

Nguyen, S.N., C. Song and M.E. Scharf. 2007. Toxicity, synergism and neurological effects of novel volatile insecticides to insecticide-susceptible and -resistant Drosophila strains. J. Econ. Entomol. 100(2): 534-544.



Dr. Aaron Gassmann at Iowa State University, and his collaborators, have been actively pursuing eNCR factors.  Current projects are focused on (i) identifying entomopathogens that cause eNCR in Bt-resistant insects and (ii) understanding the mechanistic basis of this phenomenon.

Dr. Barry Pittendrigh at UIUC, and his collaborators, are currently using a systems biology approach to understand the mechanisms by which insects develop resistance to toxins in order to identify potential target sites for the development of NCR factors.

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