MANAGING FUNGICIDE RESISTANCE

John J. Gallian, Phillip Nolte, and Jeffrey S. Miller

Resistance to fungicides in plant pathogen populations is one of the most significant problems in the area of chemical disease management. The use of fungicides will continue to play a major role in disease management for the foreseeable future, and development of strategies for resistance management will be necessary to maintain a useful arsenal of the most effective fungicides.  Such strategies are required if we are to prolong the useful life of these disease control agents.

Resistance to formerly effective fungicides has been reported from almost all crops where fungicides are used. Fungicide resistance in pathogens that infect cereal crops is not nearly as important in Idaho production systems as it may be elsewhere, but the production of sugarbeet, potato, and dry beans as well as other crops such as grapes, all require the periodic application of fungicides to ensure a quality crop.

We will showcase resistance management strategies for diseases of two crops: sugarbeet and potato. While the same resistance management principles apply, there are major differences between the two crops on what materials are available for disease control and thus for resistance management.  For instance, there are only two types of active ingredients available for sugarbeet powdery mildew and well over a dozen for potato late blight.

Although some plant diseases may be managed through the alteration of cultural practices, many diseases are only managed acceptably with the application of a chemical.  For example, cultural practices have little or no effect on sugarbeet powdery mildew. The one exception is that the disease is less severe with sprinkler irrigation than with furrow irrigation but fungicide application is still required in most cases to prevent economic loss.  There are differences in sensitivity to powdery mildew among sugarbeet cultivars, but resistance in current cultivars is not great enough to forego fungicide treatment.  Application of fungicides, therefore, is and likely will remain the principle practice for managing this disease for some time. The powdery mildews, however, are among the pathogens with the greatest potential for resistance development.

For other diseases, factors such as favorable moisture conditions due to rainfall or excessive irrigation as well as favorable temperatures and other weather-related events such as wind make major contributions to disease pressure. These factors are especially important for foliar diseases such as potato early blight and late blight. 

We need only to look a few years back to be reminded of the impact of fungicide resistance.  Bayleton was extensively used in Idaho for powdery mildew control beginning in 1982.  Rates as low as 2-4 oz/acre would give near season long control, but by 1987, increased rates were necessary to maintain control for only about three weeks.  Reduced control was primarily being blamed on low application rates and poor fungicide coverage within the crop canopy.  The manufacturer finally withdrew the Bayleton label on annual crops because of developing resistance, and there were no alternatives other than sulfur for control when the severe powdery mildew epidemic hit in 2000.  More recent problems have been encountered with strobiluron and metalaxyl/mefenoxam chemistries in potatoes.

Metalaxyl (Ridomil) was first introduced in the 1970’s as an effective tool for controlling diseases caused by oomycetes, such as late blight and pink rot of potato.  The development of resistance to metalaxyl in the late blight pathogen population was fast.  In many European countries, resistance was observed after a single year of metalaxyl use.  Withdrawing metalaxyl use in some European countries resulted in an increase of pathogen isolates sensitive to metalaxyl.  However, this did not happen in the United States.  Pathogen isolates resistant to metalaxyl increased in frequency, even in the absence of metalaxyl use.  An enantiomer of metalaxyl, mefenoxam, was released in 1997 under the trade name Ridomil Gold.  Mefenoxam was more active than metalaxyl against oomycete pathogens and many hoped that it would be effective against metalaxyl-resistant isolates of the late blight pathogen.  Unfortunately, it was not.  Isolates of the late blight pathogen in Idaho in 2000 showed that all isolates were resistant to mefenoxam, even though Ridomil Gold was not used in any of the fields reported to have late blight.

DEFINITION AND POPULATION DYNAMICS OF RESISTANCE

Fungicide resistance may be defined as the stable, inheritable adjustment by a pathogen  to a fungicide, resulting in reduced sensitivity of the pathogen to the fungicide.  Resistance development is most likely the result of a genetic mutation that gives the pathogen the ability to counteract or circumvent the activity of the fungicide.  Such mutations may not contribute to the pathogen's ability to survive under natural conditions, but allow the organism to survive when the selective pressure of the fungicide application is present. It is believed that a small, stable portion of a pathogen population contains a mutation that confers resistance to a fungicide. With intensive and repeated use of a single fungicide, the sensitive portion of the population can be destroyed, leaving only the resistant portion of the population to survive, multiply, and become dominant. 

TYPES OF RESISTANCE

Worldwide, resistance in pathogen populations to more than 135 different active ingredients has been reported. However, failure of a fungicide application to control a particular disease is not necessarily due to fungicide resistance. Poor or poorly-timed application, expired product or extremely heavy disease pressure can all be responsible for a failed application.

The most effective fungicides are those that have systemic or translaminar activity. Fungicides with this type of activity are somewhat mobile within the plant and can provide protection from the target pathogens even on portions of the plant surface that did not receive direct treatment.  These are the fungicides, unfortunately, that have the highest risk of resistance development because they have very specific modes of action. 

Resistance to some fungicides may be seen as complete loss of disease control resulting from a modification of a single major gene.  Under this system, pathogens are either resistant or sensitive to the fungicide, and the populations do not overlap.  Increasing the rate or frequency of application does not change disease control in the resistant population.  This type of resistance is referred to as “qualitative resistance.” These types of fungicides are often referred to as “single site” fungicides, because they interfere with a single metabolic pathway in the pathogen.  In this case, only a single mutation in the pathogen population is needed for resistance to develop. The development of resistance to this type of fungicide can be extremely rapid.

With polygenic resistance, there is a continuous variation in sensitivity within the population.  The resistance results from the modification of several genes, and develops somewhat gradually over time.  Increasing the fungicide application rate or the frequency of application improves performance, but continued use could eventually result in complete loss of control.  As resistance develops, the lack of control is often attributed to poor coverage, too low a rate, poor timing of application, or improper calibration.  This type of resistance is called “quantitative resistance.” Fungicides of this type are often referred to as “multisite” fungicides because they interfere with multiple metabolic sites in the pathogen. In this case, several mutations must occur simultaneously before resistance to fungicides of this type can develop. While some chemistries with multisite activity are considered at risk, there are several classes of multisite fungicides, such as the EBDC fungicides that have been in continuous use since the 1940’s with no cases of resistance having been reported to date. 

FUNGICIDE GROUPS

The most effective fungicides for plant disease control at risk for pathogen resistance to develop can be classified into 5 major chemical groups (or classes):  1) benzimidazoles, 2) dicarboximides, 3) demethylation inhibitors (DMI), 4) phenylamides, and 5) Qo inhibitors (QoI) (primarily strobilurins).  Fungicides currently available or being considered for registration for sugarbeet powdery mildew control fall into the benzimidazoles, DMI's and QoI's.  This discussion will focus on these three groups. 

Benzimidazoles.  The benzimidazoles include Benlate, Mertect and Topsin M.  Benlate is no longer being manufactured, but in addition to previous labels, Topsin M has recently received  labels for sugarbeet powdery mildew and white mold on potatoes.  The benzimidazoles are an example of qualitative resistance and represent the beginning of the most serious cases of fungicide resistance, starting in the late 1960's with powdery mildew of curcurbits in greenhouses after only one year of use.  Resistance to the benzimidazoles develops quickly, is stable, and sensitivity will usually not be restored by cessation of their use.  Resistant strains have persisted after many years of non-use.  Among the first cases of resistance to the benzimidazoles was in Cercospora on sugarbeet in Greece in 1971.  Resistance in Cercospora on sugarbeet developed to the benzimidizoles in the Red River Valley in the mid-1980’s after only three years of use.  After nearly 20 years of non-use of benzimidizoles for Cercospora control, there is some evidence that there is limited sensitivity returning to this group of fungicides in the southern Minnesota Beet Sugar Cooperative Factory District when used in combination with other fungicides. Fungicides in this group cannot be used alone.

In the early 1990’s, a similar problem occurred in the potato dry rot fungi, Fusarium sambucinum and Fusarium coeruleum, and the benzimidazole fungicides that were used to manage dry rot both on cut seed and on whole potatoes as they were placed into storage.  According to a survey of benzimidazole resistance performed by the University of Idaho from 1993-1995, nearly 85% of all F. sambucinum isolates examined were resistant.  As a result, the storage formulation of benzimidazole (Thiabendazole, Mertect 340F) is used by fewer and fewer growers and seed piece treatments such as Tops 2.5D (thiophanate-methyl) have now been combined with an EBDC fungicide (mancozeb) to produce the product known as Tops MZ (On a percentage basis, most growers use mancozeb alone.  Not much Tops MZ is used.)

Strobilurins.  The strobilurins are the primary fungicides in the Qo inhibitor group (QoI’s).  Two fungicides that recently have gained registration for powdery mildew control on sugarbeet are Headline and Gem, which both fall into this category.  Resistance in this category is qualitative, develops rapidly, and is stable once it develops.  For example, in 1999, after only 2 years of commercial use, resistant strains were found in field and greenhouse crops of melon and cucumber in Japan, Taiwan, southern Spain, and southern France.  Resistance arose independently at isolated locations rather than as the result of spread of a resistant strain.  The resistance results from a single mutation substitution of one amino acid, and resistant isolates are competitive with wild-type sensitive isolates.  

In potatoes, the strobilurin fungicide Quadris was introduced with an Emergency Use Permit in 1998.  A survey of isolates of the early blight fungus (Alternaria solani) from North Dakota, Nebraska, and Wisconsin from 2002 showed that a 10-fold decrease in sensitivity to Quadris had occurred.  Early blight control with Quadris in research plots at North Dakota State University and the University of Wisconsin was similar to disease control obtained using standard protectant fungicides.  The level of early blight control with Quadris use was not satisfactory.

Demethylation Inhibitors. The demethylation inhibitors (DMI) include Bayleton (triadimefon), Laredo (myclobutanil) and Eminent (tetraconazole), and are examples of quantitative resistance.  Resistance to the DMI’s develops slowly, is relatively unstable, and sensitivity may be restored with non-use of this group.  With the loss of Bayleton several years ago, only Laredo and Eminent are currently being considered for registration on sugarbeet, but neither of these is expected to be granted full registration until at least 2004.  There is, however, a possibility of emergency use in the interim through the Section 18 emergency exemption process.  The use of DMI’s in resistance management strategies is very valuable.

Of inestimable value to any fungicide resistance management strategy is the availability of effective fungicides that have a very low risk for resistance development. Compounds such as the dithocarbamates (EBDC compounds ie: mancozeb and metiram) and chloronitrile (chlorothalanil) have been in use for more than 50 years without a single case of resistance developing. Because of the widespread activity of these types of fungicides, there are limits on how many pounds of active ingredient can be used on a given crop in any one year and they are not approved for management of disease in all crops. In contrast, the single site types of fungicides tend to be more “silver bullet” in their activity and often target a narrow spectrum of target fungi and have little or no effect on other organisms including nonpathogens and beneficials.  They also tend to work very effectively even when applied a very low concentrations of active ingredient. The trade-off is that they are vulnerable to resistance development.

CROSS RESISTANCE AND MULTIPLE RESISTANCE

Cross Resistance. The modes of action of different fungicides within each of the groups are very similar or the same.  Any pathogen population that is resistant to one fungicide within a group will almost certainly be resistant to other members of that same group.  The issue of cross resistance adds a dimension that limits the flexibility for managing resistance. Once resistance develops to one fungicide, others in that group are likely to also become less effective or useless.

Multiple Resistance. In contrast to cross resistance, pathogen populations have been shown to develop resistance to fungicides in more than one chemical group. The intensive use of at-risk fungicides in different chemical groups without following resistance management principles can result in the development of multiple resistance. For example, curcurbit powdery mildew strains have been detected with resistance to as many as 4 classes of fungicides, including the QoI’s, benzimidazoles and DMI’s after only 2 years of intensive use in Japan, and Cercospora beticola on sugarbeet in the Red River Valley has shown  resistance to fungicides in at least 2 classes. Because of the ease of resistance developing to the benzimidazoles and strobilurins, resistance in the same pathogen to these two classes of fungicides is highly possible with sugarbeet powdery mildew. Couple multiple resistance across groups with cross resistance within groups, and the loss of efficacy for a large number of fungicides is possible.

FUNGICIDE RESISTANCE MANAGEMENT PRINCIPLES

It is essential to use a management program to prevent or delay the buildup of resistant strains.  Attempting to manage resistance after it has developed may be ineffective.  Not all of these principles are applicable to each system, but most can be implemented.   

The most important of these principles is that at-risk fungicides should be alternated with fungicides with different modes of action (different cross-resistant groups), and they should be combined or alternated with fungicides with low resistance risk.  At-risk fungicides should be used at the manufacturer’s recommended full rate and application interval.  Use of full rates is expected to minimize selection of strains with intermediate sensitivity when resistance is polygenic (quantitative resistance).  Unfortunately, the use rate that companies select for registration of a new fungicide is often the lowest rate providing consistent control.  The lowest effective rate may allow strains with intermediate resistance to survive. 

At-risk-fungicides should only be used when needed most.  The most critical time to use at-risk fungicides for resistance management is early in the epidemic when the pathogen population is low.  The tactic of using at-risk fungicides as curatives (eradicants) is inconsistent with good resistance management.  Resistance can develop quickly when fungicides are used curatively because far higher numbers of the pathogen are available for selection and survival, and intermediate resistance can more easily be selected.

Understanding the mode of action of available fungicides is important. The risk of resistance developing and remaining stable for long periods is greatest with the qualitative resistance groups benzimidazoles and QoI’s. For some fungicide/pathogen management situations, there may be only a limited number of options for tank mixing or alternation of fungicides such as with powdery mildew of sugarbeet. Because there has never been a case of resistance developing to sulfur, tank mixing sulfur with any at-risk fungicide as a standard practice for this disease will give good control and can be very helpful in resistance prevention.  The cost of adding sulfur as a tank mix is very small.   In these situations it is of utmost importance that resistance management guidelines be carefully followed.

SUMMARY

·        New fungicides with specific modes of action have the propensity for resistance to develop in the target pathogens.  Failure to follow resistance management guidelines carefully will likely result in the loss of these new fungicides as effective control measures

·        It is essential to use a management program to prevent or delay the buildup of resistant strains.  Attempting to manage resistance after it has developed is far more difficult than prevention. 

·        Mixtures of an at-risk fungicide should be used with a companion fungicide that is not cross-resistant or, if available, with a multisite material such as an EBDC. 

·        Alternate applications should be made using fungicides with different modes of action.

·        It is best to limit at-risk fungicides to just a few applications per year.  The same fungicide, or fungicides with the same mode of action, should never be used consecutively.

·        Avoid using benzimidazoles and QoI’s in the same growing season to reduce the likelihood of developing multiple resistance.

·        At-risk fungicides should be used early in the epidemic when the pathogen population is low.  Curative (eradicant) treatments should be avoided because they select for intermediate resistance.

·        At-risk fungicides should be used at the manufacturer’s recommended full rate and application interval.  Reduced rates will likely select for populations of intermediate resistance.

·        Continuing the alternation practice into the following year may be advantageous.

AUTHORS

John J. Gallian, Sugarbeet Specialist and Plant Pathologist; University of Idaho, Twin Falls Research and Extension Center, PO Box 1827, Twin Falls, ID  83303-1827, Phone: (208) 736-3633

Phillip Nolte, Extension Seed Potato Specialist and Plant Pathologist, University of Idaho, Idaho Falls Research and Extension Center, 1776 Science Center Dr., Idaho Falls, ID 83402, Phone (208) 529-8376

Jeffrey S. Miller, Potato Pathologist, University of Idaho, Aberdeen Research and Extension Center, 1693 S 2700 W, Aberdeen, ID 83210, Phone: (208) 3974-4181

 FURTHER READING

Fungicide resistance in North America. 1988. C.J. Delp, ed. APS Press, St. Paul, MN, 133 pg.

McGrath M. T. 2001. Fungicide resistance in curcurbit powdery mildew: Experiences and challenges. Plant Dis. 85:236-245.