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Pesticide Resistance: Strategies and Tactics for Management.
1986. National Academy Press, Washington, D.C.
Preventing and Managing
Fungicide Resistance
JOHAN DEKKER
Following a description of the term fungicide resistance, the fac-
tors that govern the buildup of a resistant pathogen population in
the field are covered. Short-term tactics and long-term strategies to
counteract the development of resistance are discussed.
INTRODUCTION
When fungicide resistance became a problem shortly after the introduction
of systemic fungicides in the 1960s, the reliability of chemical disease control
was at stake, especially since we did not know how to cope with the problem.
Farmers who saw that a fungicide was becoming less effective often increased
the dose, thus increasing the selection pressure and aggravating the problem.
The failure of some of the new, originally very effective fungicides to
control disease was a surprise, and it created doubt about effective disease
control using these fungicides. To better understand the resistance phenom-
enon, biochemical and genetic studies were conducted. These studies revealed
the mechanism of action of several new fungicides and the mechanism of
resistance in fungi. Greenhouse and field experiments on the ecological and
population aspects of resistance have yielded considerable information about
fungicide resistance.
This paper will discuss (1) the possibilities of using this information to
develop tactics for preventing and managing fungicide resistance, (2) the
research needed for further development and improvement of these strategies,
and (3) what new approaches might offer prospects for dealing with the
fungicide resistance problem.
347
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TACTICS FOR PREVENTION AND MANAGEMENT
FUNGICIDE RESISTANCE
People define fungicide resistance in different ways, depending on their
interests and concerns. Fungicide resistance occurs when a fungal cell or a
fungal population that originally was sensitive to a fungicide becomes less
sensitive by hereditable changes after a period of exposure to the fungicide.
A panel of FAO (Food and Agriculture Organization of the United Nations)
experts has recommended that the word "resistance" should apply only to
a hereditable decrease in sensitivity. The word "tolerance" should not be
used in this sense, since it is ambiguous (FAO, 19791. Use of the word
"insensitivity" in place of resistance is also not recommended, because it
suggests a complete loss of sensitivity, which occurs only rarely.
The researcher first speaks of resistance after the emergence of less-sen-
sitive cells has been observed in a petri dish and the hereditable nature of
this phenomenon has been proved or seems likely. Resistance in the labo-
ratory, however, does not mean that resistance will develop in the field.
More important is a shift toward lower fungicide sensitivity in a field pathogen
population, which may be called development of resistance, even if the
fungicide still provides satisfactory disease control. The farmer speaks of
fungicide resistance only when disease control fails. This definition is also
often used by the agrochemical industry and the extension officer, who may
be afraid that reports about laboratory resistance before problems in the field
have occurred may confuse or even alarm the farmer. Because of the various
meanings, one must define which type of resistance is being discussed:
emergence of resistant cells in laboratory experiments; reduction of fungicide
sensitivity in the field, but still with adequate control; or field resistance with
loss of disease control.
BUILDUP OF A RESISTANT POPULATION
As Georgopoulos pointed out (this volume), the main mechanisms of
resistance to fungicides are a change at the site of action in the fungal cell
that decreases its affinity to the fungicide or a change in uptake of the chemical
so that less of it reaches the site of action. Detoxification has rarely been
reported as the cause of resistance in fungi, although it is the main mechanism
of resistance in insects.
Resistant populations develop and increase in different ways, often from
forces we can control. The mechanism of resistance may influence the fitness
of resistant cells, as compared with sensitive cells, which is important to the
buildup of a resistant pathogen population. The fitness of resistant strains
appears to vary considerably for different types of fungicides. For some,
resistance appears to be linked to a decrease in fitness in the absence of the
fungicide. Thus, fungicides may be classified as low-risk, moderate-risk, or
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FUNGICIDE RESISTANCE
349
high-risk compounds (Dekker, 19841. With insecticides loss of fitness in
resistant insects plays a lesser role. Here the strategy has been to change to
an insecticide with a different mechanism of action. This strategy is possible
only so long as new insecticides become available. The discovery of fun-
gicides with a lower resistance risk offers possibilities for developing strat-
egies to prolong their use.
The life cycle of the pathogen and the nature of the disease may influence
the speed of buildup of a resistant pathogen population. For example, resis-
tance builds more rapidly in an abundantly sporulating pathogen on aerial
plant parts than in a slowly expanding soil pathogen. Environmental con-
ditions that increase the severity of the disease may also speed the devel-
opment of resistance. Another important factor in this respect is the management
of pesticide application: a continuously high selection pressure by one chem-
ical or by more chemicals with the same mechanism of action favors the
buildup of a resistant pathogen or insect population.
SHORT-TERM TACTICS
New Chemicals
It would be very valuable to have information on the probability of resis-
tance before a new chemical is used in the field. For example, experiments
on an artificial medium, with or without mutagenic agents, may tell us
whether emergence of resistant cells (by mutation or otherwise) is possible.
If such experiments do not yield resistant cells, their emergence in the field
should not be expected, but if they do, further testing should be done on the
fitness of the resistant cells on the plant, compared with that of the wild-
type fungus. Such experiments may give an indication of the resistance risk
of the fungicide and could be used in devising strategies to minimize the
chance of resistance.
Unfortunately, even when all possible laboratory and greenhouse experi-
ments have been carried out, it is rarely possible to precisely predict what
is going to happen in the field. Greenhouse conditions are never exactly the
same as field conditions. Field experiments are indispensable, and they should
be accompanied by careful monitoring (as outlined by Keiding, this volume).
But even field experiments may not yield the results that can be obtained
from large-scale application in practice, because the size of the area treated
may play a role in the buildup of resistance. Thus, even if no resistance
develops in laboratory, greenhouse, or field experiments, resistance could
still appear in practice. For instance, with dodine and Kitazin-P, resistance
problems arose only after many years. Nevertheless, experiments may in-
dicate some of the risks involved, which is important for devising tactics to
prevent or delay resistance.
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TACTICS FOR PREVENTION AND MANAGEMENT
High-Risk Chemicals
High-risk compounds, such as the benzimidazole and acylalanine fungi-
cides, should not be used to control risky diseases when other, less-risky
chemicals provide satisfactory control. Diseases are considered risky when
they allow a rapid buildup of a resistant pathogen population, for example,
by a repeating infection cycle during the growing season with an abundant
spore production. Other diseases may be less risky, for example, those caused
by root and foot pathogens. If a high-risk fungicide is applied to control a
risky disease, stringent tactics should be used to minimize the chance for
development of resistance. To avoid having such fungicides and related
chemicals exert a constant selection pressure, therefore, one must remember
the following factors.
· The amount of fungicide at risk applied to the crop should not exceed
the minimum dose necessary for adequate disease control.
· The mode of application should be considered, for example, soil drench
may allow uninterrupted uptake of the chemical and a prolonged period of
selection pressure by the fungicide.
· Use of one particular fungicide or related fungicides for preharvest and
postharvest application should be avoided, since the former may select for
resistant cells, leading to problems in subsequent postharvest treatments.
· Treatment of a large area (e.g., all fields with a particular crop in one
region or country) with the same or related fungicides should be avoided.
No sensitive forms will then be available to enter the crop from outside,
which limits the competition between sensitive and resistant forms during
intervals of low selection pressure.
· A very thorough treatment of the crop, with little or no escape of
sensitive cells, will eliminate competition between resistant and sensitive
cells and thus favor the former.
~ The selection pressure exerted by a chemical at risk may be reduced by
rotation or combined use of chemicals or by integrating chemical control
with other control measures.
Rotation or Combination
Rotations or combinations of fungicides can reduce the risk of resistance,
but only when certain guidelines are followed. To reduce selection pressure
the fungicides should possess different mechanisms of action. Using two
risky chemicals together is not recommended: the population of fungal cells
is usually so high that the chance exists for simultaneous mutations in different
genes toward resistance to both chemicals. One of the fungicides in the
mixture should pose little or no risk, although the use of a mixture will not
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FUNGICIDE RESISTANCE
TABLE 1 Spraying Schemes and Risk for Development of Fungicide
Resistance
351
Type Program Risk
. . .
a S - S - S -S Highest Risk
b S - C - S -C Alternation
c (S + C) - (S + C) - (S + C) - (S + C) Mixture
d (S+C) - C - (S+C) - C Combination b and c
e C - C - (S+C) - C Lowest Risk
S = Fungicide at risk.
C = Conventional fungicide.
SOURCE: Dekker (unpublished).
always stop the buildup of resistance to the compound at risk: resistance may
occur in the pathogen population that is not eliminated by the nonrisky
compound. Under certain conditions buildup of resistance in a mixture may
occur at the same speed as when the compound is used alone (Kable and
Jeffery, 1980~. Theoretically this happens when there is no escape, that is,
when there are no fungal cells that are not hit by the fungicide mixture and
when selection pressure is not reduced during spray intervals. Such situations
are rare-e.g., with postharvest treatment of citrus fruit (Eckert, 1982)
and usually do not occur in the field. In most cases the use of a mixture in
the field will at least delay the buildup of resistance. If resistant strains have
a reduced fitness, compared with sensitive strains, and if the interval between
applications of the fungicide at risk is large enough to allow the proportion
of the resistant pathogen population to drop to the preceding level, resistance
problems might be avoided indefinitely.
A resistant population may build up gradually in an alternation or rotation
scheme. During the period that the nonrisky compound is used, the proportion
of resistant strains will not increase, and may decrease if there is reduced
fitness. Resistance could then be postponed indefinitely, depending on the
degree of reduction in fitness and the length of the intervals between sprays
of the compound at risk. The mixture may provide longer delay of resistance
at higher escape; the alternations may provide more delay at lower escape
(Kable and Jeffery, 19801.
Both mixtures and alternations have some disadvantages. In mixtures the
compound at risk is always present, which means constant selection pressure
if the application is not interrupted. In an alternating scheme the use of the
nonrisky compound is interrupted for no good reason. These disadvantages
may be decreased by combining mixtures and rotations such that the nonrisky
compound is constantly present and only the use of the risky compound is
interrupted (Dekker, 19821. The chance for buildup of resistance may be
delayed further by using the mixture only in critical situations (Table 11.
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TACTICS FOR PREVENTION AND MANAGEMENT
Low- or Moderate-Risk Chemicals
A fungicide may be at low risk when resistant strains show a strongly
reduced fitness in greenhouse experiments or when it has been used for a
few years without resistance problems. Because resistance could develop in
later years, fields should be monitored. Monitoring will show whether a shift
toward reduced sensitivity of the pathogen population occurs during the
growing season or during consecutive seasons. Depending on the degree of
this shift, measures (as discussed above for the risky compounds) can be
taken to prevent or delay the buildup.
LONG-TERM STRATEGIES
To prevent or delay the buildup of a resistant pathogen population, different
chemicals that are effective against a particular disease must be available.
One way of increasing the number of available chemicals is to search for
new site-specific inhibitors. Before the introduction of fungicides with site-
specific action, little was known about the metabolic differences between
the cells of a pathogen and a host, with the exception of the wall-constituent
chitin, present in most fungi but not in plants. This difference is exploited
by the polyoxin antibiotics, which interfere with chitin synthesis in the fungal
cell wall. Examples of sites found since then include differences in tubulins
constituting the spindle in fungi and plants; differences in sterols, namely
ergosterol in fungi versus lanosterol in plants; and differences in the protein
synthesizing apparatus, in the respiratory chain, or in enzymes involved in
RNA synthesis between plants and certain fungi. More such sites will prob-
ably be discovered. Special attention should be given to site-specific inhib-
itors that show a low risk to development of resistance.
Further, the search should be intensified for disease-control agents that
are not fungicidal in vitro, but increase the resistance of the host plant or
decrease the pathogenicity of the parasite. Some of these chemicals might
not or might less-readily encounter resistance.
Another concept is that of developing compounds with negatively corre-
lated cross-resistance: a mutational change in a pathogen that confers resis-
tance to fungicide A and, at the same time, increased sensitivity to fungicide
B. and vice versa. Thus, when a combination of A and B is used, B will
eliminate strains resistant to A, and A will eliminate strains resistant to B.
Several combinations of such compounds have been described in the liter-
ature, but in most cases the phenomenon did not occur with all resistant
strains. Moreover, occurrence of other resistance mechanisms, which do not
result in negative cross-resistance to A and B. cannot be excluded. Never-
theless the phenomenon deserves further exploration.
Another phenomenon is synergism between two fungicides, A and B.
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FUNGlClDE RESISTANCE
353
especially if A is more active on strains resistant to B than on wild-type
strains. The effect of respiration-inhibiting fungicides on fenarimol-resistant
strains of Aspergillus nidulans and Penicillium italicum illustrates such syn-
ergism (de Waard and Dekker, 19831. Fungicide-resistant strains do not
accumulate fenarimol, due to the presence of a constitutive energy-dependent
efflux. Adding a respiration-inhibiting compound results in fenarimol ac-
cumulation and fungicide sensitivity. Researchers should further explore the
existence of additional combinations of compounds that might counteract
resistance in a similar way.
The search for integrated disease-control measures should be intensified.
The use of cultivars with a certain degree of natural resistance, cultural
practices, and biological control measures might be integrated with chemical
control. For example, microorganisms used for biological control could be
made resistant to a fungicide so that both can be used at the same time
(Papavizas et al., 19821.
In addition to strengthening our research efforts, we must ensure that the
number of conventional, nonsystemic fungicides is not needlessly decreased
by regulatory agencies. Although these chemicals cannot perform all the
tasks of systemic fungicides, they remain a reliable and invaluable tool for
controlling disease when resistance to a new specific compound occurs. They
can also be used as companion compounds of systemic fungicides, in mix-
tures, or in rotation.
The need for a varied arsenal of fungicides to cope with fungicide resistance
requires that barriers for introducing new chemicals are not made higher than
necessary. The risks of a new fungicide to nontarget organisms and the
environment should be carefully weighed against the benefits. Not using
chemicals is risky, not only for the economy and world food production but
also for toxicological reasons: some fungi occurring in the crop or in the
harvested product may produce mycotoxins, of which some may be carcin-
ogenic. A senate committee appointed by President Kennedy, reporting on
pesticides and public policy after the appearance of Rachel Carson's book
Silent Spring, stressed the importance of a balanced benefit-risk equation
and noted that the public lacked information concerning stringent precautions
taken by the government to limit possible risks of the application of pesticides
(U. S. Senate, 19661.
Finally, any long-term strategy must create possibilities for implementing
tactics to prevent and manage fungicide resistance. We must develop an
efficient system to communicate information among growers, extension of-
ficers, teachers, research workers, manufacturers, salesmen, the press, reg-
ulatory agencies, and the government. One example of an information
distribution effort was the International Course for Southeast Asia on Fun-
gicide Resistance in Crop Protection, held in Malaysia from October 17 to
24, 1984. The course was organized by the crop protection departments of
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TACTICS FOR PREVENTION AND MANAGEMENT
the agricultural universities at Wageningen, the Netherlands, and at Serdang,
Malaysia, in collaboration with the Food and Agricultural Organization, the
Chemical Control Committee of the International Society of Plant Pathology,
and the Fungicide Resistance Action Committee of the International Group
of National Associations of Agrochemical Manufacturers.
CONCLUSION
Although it is not yet possible to predict the development of resistance to
a new fungicide with certainty, as much information as possible should be
obtained about the potential of plant pathogens to become resistant to such
a fungicide. This can be done in appropriate laboratory, greenhouse, and
field experiments.
If fungicides are applied that have been proved to be risky with respect
to development of resistance, it is of prime importance to avoid a continuous
and high selection pressure by such fungicides by using different fungicides
in a mixture or in alternation. For flexible management it is also important
to have a range of chemicals available. This can be achieved by the devel-
opment of more fungicides with different mechanisms of action and by a
reticent policy with respect to Reregistration of old, conventional fungicides.
In order to alleviate the resistance problem in the future, attention should
also be given to disease-control agents that increase the resistance of the host
plant and to the phenomena of synergism and negatively correlated cross-
resistance.
REFERENCES
Dekker, J. 1982. Counter measures for avoiding fungieide-resistanee. Pp. 177-186 in Fungieide-
Resistanee in Crop Proteetion, J. Dekker and S. G. Georgopoulos, eds. Wageningen, Netherlands:
Centre for Agrieultural Publishing and Documentation.
Dekker, J. 1984. The development of resistance to fungicides. Prog. Pest. Bioehem. Toxieol. 4: 165-
218.
de Waard, M. A., and J. Dekker. 1983. Resistance to pyrimidine fungicides which inhibit ergosterol
biosynthesis. Pp. 43-49 in Human Welfare and the Environment, Vol. 3, Y. Miyamoto and
P. C. Kearney, eds. Oxford: Pergamon.
Eekert, J. W. 1982. Penieillium decay of citrus fruits. Pp. 231-250 in Fungieide-Resistanee in Crop
Proteetion, J. Dekker and S. G. Georgopoulos, eds. Wageningen, Netherlands: Centre for Ag-
rieultural Publishing and Documentation.
Food and Agriculture Organization. 1979. Pest resistance to pesticides and crop loss assessment.
FAG Plant Prod. and Prot. Paper, No. 6/2.
Kable, P. F., and H. Jeffery. 1980. Selection for tolerance in organisms exposed to sprays of biocide
mixtures: A theoretical model. Phytopathology 70:8-12.
Papavizas, G. C., J. A. Lewis, and T. H. Abd-el Moity. 1982. New biotypes of Trichoderma
harzianum with tolerance to benomyl and enhanced biocontrol activities. Phytopathology 72: 126-
132.
U.S. Senate, Committee on Government Operations. 1966. Report on Pesticides and Public Policy.
Washington, D.C.: U.S. Government Printing Office.
Representative terms from entire chapter:
selection pressure
