Chemical control of plant diseases

Transcription

1 J Gen Plant Pathol (2013) 79: DOI /s REVIEW FOR THE 100TH ANNIVERSARY Chemical control of plant diseases Takashi Hirooka Hideo Ishii Received: 6 January 2013 / Accepted: 5 May 2013 / Published online: 6 August 2013 Ó The Phytopathological Society of Japan and Springer Japan 2013 Abstract As the world population increases, we also need to increase food production. Chemical control has been critical in preventing losses due to plant diseases, especially with the development of numerous specificaction fungicides since the 1960s. In Japan, a hostdefense inducer has been used to control rice blast since the 1970s without any problems with resistance development in the pathogen. Leaf blast has been controlled using a labor-saving method such as the one-shot application of a granular mixture of fungicide and insecticide to nursery boxes, which became mainstream in the 2000s. However, the need for many choices of fungicides that have several modes of action was demonstrated by the development of resistance to cytalone dehydratase inhibitors. In Europe, many pathogens have threatened cereals since the great increase in cereal production in 1970s, creating a large market for broadspectrum fungicides. In Brazil, Phakopsora pachyrhizi was distributed to large soybean acreages during 2000s, and the outbreak of soybean rust resulted in a large increase in fungicide use. While the importance of chemical control is recognized, fungicide resistance is an avoidable problem; published guidelines on countermeasure and manuals on testing sensitivity to fungicides are available. Since chemical regulations have become stricter, new fungicides are less likely to be developed. Our task is to maintain the effectiveness and diversity T. Hirooka (&) Nihon Nohyaku Co., Ltd, Kyobashi , Chuo-Ku, Tokyo , Japan hirooka-takashi@nichino.co.jp H. Ishii National Institute for Agro-Environmental Sciences (NIAES), Kannondai 3-1-3, Tsukuba, Ibaraki , Japan of the present modes of action for fungicides and implement countermeasures against the development of fungicide resistance. Keywords Fungicide Mode of action Fungicide resistance Chemical control Rice blast Host-defense inducer Introduction For plant disease control, chemicals are a critical element in effective integrated pest management (IPM) programs. Chemical control began with the introduction of lime sulfur and Bordeaux mixture in the mid-1800s, and fungicides that have multiple sites of action with protective and contact properties against several target sites in fungal metabolism played a leading role in the first half of the 1900s. Fungicides that inhibit a specific target site were introduced in the 1960s. Many specific fungicides have protective and curative properties with systemic action, giving users flexible application windows and became a mainstay until recently (Knight et al. 1997; Morton and Staub 2008). After the research and development process for a fungicide is finalized by a company, the product must then be registered in each country before it can be used by growers. The present review describes the trends in chemical controls from the last five decades and discusses (1) fungicide markets, (2) fungicide groups by mode of action, (3) practical examples of chemical controls, which include rice blast and issues surrounding chemical control in Japan, cereal diseases in Europe, and soybean diseases in Brazil, and (4) fungicide resistance and countermeasures in Japan.

2 J Gen Plant Pathol (2013) 79: Fig. 1 Fungicide market for crop use by region in 1999 and 2010 (Phillips McDougall 2000, 2011). NAFTA includes the US, Canada and Mexico Fungicide market World sales of fungicides for crop use totaled US$9.91 billion in 2010 and have increased by 6.5 % annually since Major targeted crops include pome fruits (24 %), cereals (23 %), soybean (12 %), vine (10 %), rice (8 %), potato (7 %), maize (4 %), and rape (3 %) (Phillips McDougall 2000, 2011). Fungicide sales in every region in 2010 increased over 1999 sales (Fig. 1). In Latin America, use tripled because of an outbreak of soybean rust in Brazil. Sales in Asia in 2010 were the same as those in Latin America. Fungicide sales increased in Asia, China and India and in developing countries in Southeast Asia. The Japanese fungicide market, occupying half of the Asian market, comprised solo products and mixtures with insecticides. Sales of solo products for fruits, vegetables and upland crops in Japan reached 74 billion yen in 2010 but declined gradually as agriculture waned with the aging of farmers, decreases in the workforce, and increases in agricultural imports. Sales of mixtures with insecticides used mainly in paddy rice fields totaled 33 billion yen and have remained constant over the past 10 years (Japan Plant Protection Association 2012). Fungicide groups classified by mode of action Commercial fungicides are summarized based on mode of action, percentage of sales, market-entry time, and spectrum of efficacy in Table 1. The international Fungicide Resistance Action Committee (FRAC) has grouped fungicides according to target site, and FRAC codes assist farmers in managing fungicide resistance (FRAC Code List 2013). The classification in Table 1 uses the FRAC criteria for reference. Although fungicides are classified roughly in terms of specific-target fungicides and conventional multi-site fungicides, the sterol demethylation inhibitors (DMIs) and quinone outside inhibitors (QoI) are representative of specific fungicides and account for approximately half of the total fungicide sales. Meanwhile, multi-site fungicides, including dithiocarbamates (mancozeb), inorganic (copper and sulfur formulations), phthalimides (captan) and chloronitriles (chlorothalonil) account for roughly one-fifth of fungicide sales and are still on the increase. To control many plant pathogens, multi-site fungicides are necessary, and special efforts are engaged to maintain the registration in many countries based on safety. In addition, specific fungicides with new modes of action are greatly desired to maintain diversity in the mode of action, which is critical for managing the development of fungicide-resistance pathogens. Sterol biosynthesis inhibitors (SBIs) SBIs are classified into FRAC mode of action groups G1, G2, G3 and G4 according to different target sites within the sterol biosynthesis pathway. Those in G1, G2 (amines including spiroxamine) and G3 (hydroxyanilides) are used as agrochemicals. Those in G4 are used only as pharmaceuticals. Since the target site of fungicides in G1 is sterol C14 demethylase, they are named demethylation inhibitors (DMIs). DMIs account for almost 90 % of the SBIs, and most belong to one chemical class, the triazoles, which in include the top three compounds in sales, tebuconazole, epoxiconazole and prothioconazole, followed by the next three in sales, difenoconazole, propiconazole and cyproconazole. In addition, metconazole (Sampson et al. 1992) is one of the major fungicides for the control of Sclerotinia rot on rape and Fusarium head blight (FHB) on cereals in Europe. Aside from the triazoles, there are four chemical classes: imidazoles (triflumizole), pyrimidines, pyridines and piperazines. SBIs have a broad spectrum of efficacy, protective and curative properties, systemic action, long-lasting activity, and field resistance is relatively slow to develop (Kuck et al. 2012b). In Japan, DMIs are used on fruits, vegetables, tea plants, cereals and ornamentals and as seed treatments. Representative DMIs include triflumizole (Hashimoto et al. 1986), tebuconazole and difenoconazole. Other products discovered by Japanese companies, include pefurazoate (Wada et al. 1991) and ipconazole (Tateishi et al. 1998), used as rice seed treatments and imibenconazole (Ogawa 1995), oxpoconazole fumarate (Morita and Nishimura 2001) and simeconazole (Tsuda et al. 2000) used primarily on fruits and vegetables. QoIs QoIs, known as strobilurins, started to be used in the 1990s and have become the most important fungicides after the

3 392 J Gen Plant Pathol (2013) 79: Table 1 Mode of action (Fungicide Resistance Action Committee 2013; Kuck et al. 2012a; Phillips McDougall 2010), market share in 2009, year introduced and spectrum of efficacy of major fungicide groups Fungicide group Mode of action Market share Year introduced Spectrum of efficacy Target site code FRAC code (% of total) 2009 Demethylation inhibitors (DMIs) G s A, B, D Quinone outside inhibitors (QoIs) C s A, B, D, O Dithiocarbamates Multi-site M3 6.8 *1950s A, B, D, O Inorganic Multi-site M1, M2 4.7 *1950s A, B, D, O Phthalimides Multi-site M4 4.2 *1950s A, B, D, O Benzimidazoles and thiophanates B s A, B, D Succinate dehydrogenase inhibitors (SDHIs) 1st generation C s B a SDHIs 2nd generation 1980s B a SDHIs 3rd generation 2000s A, B, D Chloronitriles Multi-site M5 3.2 *1950s A, B, D, O Phenylamides A s O Amines G s A, B, D Carboxylic acid amides (CAAs) H s O Dicarboximides E s A Anilinopyrimidines D s A Others (cymoxanil) Unknown s O Others (fosetyl-aluminium) Unknown s O Others (fluazinam) C s O, A, D Others (host defense inducers) P1, P2, P3 P 1970s Magnaporthe Others (melanin biosynthesis I1, I2 16.1, s Magnaporthe inhibitors [MBIs]) Others (uncouplers, phosphonate, other Multi-site, cyanoacetamide oximes, etc.) A1 RNA polymerase I, B1 b-tubulin assembly in mitosis, C2 complex II: succinate-dehydrogenase, C3 complex III: cytochrome bc1 (ubiquinol oxidase) at Qo site, C5 uncouplers of oxidative phosphorylation, D1 methionine biosynthesis, E3 MAP/histidine-kinase in osmotic signal transduction, G1C14-demethylase in sterol biosynthesis, G2 D 14 -reductase and D 8? D 7 -isomerase in sterol biosynthesis, H5 cellulose synthase, I1 reductase in melanin biosynthesis (MBI-R), I2 dehydratase in melanin biosynthesis (MBI-D), P1 salicylic acid pathway, P2 unknown, P3 unknown, Multi-site multi-site contact activity, A ascomycetes, B basidiomycetes, D deuteromycetes, O oomycetes a Notably Rhizoctonia spp. SBIs in the last 20 years. They act by inhibiting the oxidation of ubiquinol at the Quinone outside (Qo) binding site on the cytochrome bc1 complex, which is located in the inner mitochondrial membrane of fungi (Knight et al. 1997). Features common to QoIs are: (1) They are derived from natural products. (2) They have been chemically optimized to overcome instability in light and toxicity to mammals. (3) They are broad spectrum, (4) with protective and curative properties and (5) systemic action. (6) Field resistance can develop quickly. (7) They delay senescence (Sauter 2012). Azoxystrobin and kresoxim-methyl were introduced to the market in the 1990s. Currently, azoxystrobin, pyraclostrobin, which replaced kresoxim-methyl, and trifloxystrobin are the top three QoIs, followed by fluoxastrobin, picoxystrobin and dimoxystrobin. In Japan, azoxystrobin and kresoxim-methyl account for 70 % of the QoI market, followed by trifloxystrobin and pyraclostrobin. They are used on fruits, vegetables, tea plants, cereals and ornamentals. On Japanese rice, azoxystrobin, metominostrobin (Masuko et al. 2001) and orysastrobin (Stammler et al. 2007) are used. The newest QoI fungicide, pyribencarb (Kataoka et al. 2010), launched in 2012, has a binding site that is assumed to differ slightly from that of the other QoIs. Benzimidazoles and thiophanates This group of specific fungicides, introduced about 1970, includes thiophanate-methyl, carbendazim and benomyl as representatives. They inhibit b-tubulin assembly during mitosis and were first used to control gray mold and apple

4 J Gen Plant Pathol (2013) 79: scab, but the pathogens rapidly developed field resistance, and they are now widely used in their relative crop segments because of their broad spectrum. Though benomyl sales have decreased since registration was cancelled in the European Union and the US (Phillips McDougall 2011), thiophanate-methyl meets the strict criteria for registration in Japan, the European Union and the US, and its use has been increasing to control Sclerotinia rot of soybean in Brazil and deoxynivalenol (DON) levels on cereal grains in the European Union (Hamamura 2012). Succinate dehydrogenase inhibitors (SDHIs) This group inhibits succinate dehydrogenase in complex II of the mitochondrial respiratory chain. Development of SDHIs can be tracing back to three generations. The first generation (e.g., carboxin) was developed in the 1960s and used as a seed treatment against Rhizoctonia spp. Representative of the second generation, mepronil (Kawada et al. 1985) and flutolanil (Araki and Yabutani 1981; Hirooka et al. 1989) were introduced in the 1980s, followed by furametpyr (Oguri 1997) and thifluzamide (O Reilly et al. 1992) in 1990s. They are also active against basidiomycetes, notably Rhizoctonia spp. and are used to control rice sheath blight, another important disease of rice in Japan. Flutolanil is used to control potato black scurf in Europe and Rhizoctonia disease of peanuts, potato, and turf in the US. The leading products of the third generation of SDHIs are boscalid and penthiopyrad (Yanase et al. 2007). Their chemical structures are closely related to the older compounds, but their spectrum of efficacy has broadened to include ascomycetes. Since these findings, several companies have intensified their research and development on this group, and new active ingredients such as isopyrazam, bixafen, penflufen, sedaxane, fluxapyroxad, benzovindiflupyr and fluopyram are reportedly ready to be launched. Only fluopyram is a pyridinyl-ethyl benzamide, as opposed to the other third generation compounds, which are carboxamides. For boscalid synthesis, a palladium-catalyzed coupling reaction was the first use of a coupling reaction in large-scale agrochemical synthesis (Rheinheimer et al. 2012). This contribution to the agricultural chemical industries was one of the achievements recognized when the Nobel Prize in Chemistry was awarded to Ei-ichi Negishi and Akira Suzuki in Japan and Richard F. Heck in the US in Other groups The broad-spectrum fungicides dicarboximides, including procymidone (Oguri and Takayama 2003), iprodione and vinclozolin, and the benzimidazoles were used to control of Botrytis on vines, fruits and vegetables in the 1980s. After resistance to them developed, the anilinopyrimidines, including cyprodinil, mepanipyrim (Maeno et al. 1990) and pyrimethanil, were introduced in the 1990s and have been used to control strains with multiple resistances to dicarboximides and benzimidazoles (Gisi and Müller 2012). Specific fungicides to control oomycete plant diseases include the phenylamides such as metalaxyl-m (Müller and Gisi 2012), Quinone inside inhibitor (QiI) fungicides such as cyazofamid (Mitani et al. 1998) and amisulbrom (Honda et al. 2007), and carboxylic acid amides (CAA) (Gisi et al. 2012) such as dimethomorph, benthiavalicarb-isopropyl (Miyake et al. 2005) and mandipropamid. There are also fungicides with unknown modes of action: cymoxanil and fosetyl-aluminum. Last, a relatively broad-spectrum fungicide, fluazinam (Komyoji et al. 1995), is classified as medium risk for resistance and is thus used globally to control potato late blight, downy mildews and gray mold. In Japan and Korea, host defense inducers and melanin biosynthesis inhibitors (MBIs) have become widely used as major countermeasures against rice blast. They have protective activity against the rice blast pathogen, Magnaporthe oryzae, without directly inhibiting fungal growth in vitro. Host defense inducers prevent rice plants from infection by M. oryzae by inducing a resistance reaction in the plants (Hirooka and Umetani 2004; Iwata 2001). They are defined by FRAC as follows: code P1, acibenzolar- S-methyl; code P2, probenazole (Iwata 2001); and code P3, tiadinil (Hirooka and Umetani 2004) and isotianil (Toquin et al. 2012) (Table 1). Although details of their modes of action have been reviewed elsewhere (Toquin et al. 2012; Yamaguchi and Fujimura 2005), a point to highlight is that the leading compound among the host defense inducers, probenazole, because of its unique mode of action was discovered in Japan and has been in practical use in Japanese rice culture since the mid-1970s. MBIs inhibit appressorial penetration of rice by M. oryzae by inhibiting pigmentation of the appressoria (Yamaguchi and Fujimura 2005). They are divided into two groups: polyhydroxynaphthalene reductase inhibitors (MBI-R) such as tricyclazole, pyroquilon and phthalide (Chida and Sisler 1987) and scytalone dehydratase inhibitors (MBI-D) such as carpropamid (Kurahashi et al. 1999), diclocymet (Manabe et al. 2002) and fenoxanil (Sieverding et al. 1998). Practical examples of chemical control Chemical control of rice blast in Japan Rice blast is the most economically important disease in Japanese rice culture and occurs in large outbreaks once to

5 394 J Gen Plant Pathol (2013) 79: twice in every 10 years (Fig. 2). Because chemical control of rice blast has been the most pertinent task for rice culture in Japan, many fungicides have been developed and introduced (Yamaguchi and Fujimura 2005). Until 1990, systematic, protective applications for rice blast control were established as follows: (1) foliar spray with dust, suspension concentrate or emulsifiable concentrate formulations of fungicides such as kasugamycin, fthalide, tricyclazole, ferimzone (Matsuura et al. 1994), (2) into-water application of granular formulations of fungicides such as probenazole, isoprothiolane (Hirooka et al. 1982), whose target site is phospholipid biosynthesis, or pyroquilon to the paddy water, or (3) an appropriate combination of the foliar spray and into-water application. Around 1990, blast-susceptible rice varieties were widely grown because consumers preferred them; thus, chemical control became even more important as blastresistant rice varieties fell out of favor. In 1993, Japan had so many rainy days that there were fewer opportunities to apply foliar sprays, and the incidence of rice blast increased explosively. Under such circumstances, the intowater applications of probenazole granules to paddy water were less affected by the weather and had excellent protective efficacy. After 1993, foliar sprays were substantially replaced by the into-water application of granules to control rice leaf blast. Meanwhile, environmentally friendly agriculture with fewer applications of chemicals was strongly promoted, and the development of labor-saving control methods was also requested. In 1998, a granular formulation of carpropamid mixed with insecticides for nursery box application was launched and provided long-lasting efficacy against leaf blast and a variety of pests with a one-shot application at transplanting. A new granular formulation of probenazole with sufficient crop tolerance was developed for nursery box about the same time, then tricyclazole, diclocymet, tiadinil, pyroquilon, orysastrobin and finally isotianil came into the market during the 2000s. The oneshot application of granules with long-lasting efficacy at or before transplanting became the mainstream for the control of leaf blast. At present, new slow-releasing granular formulations of fungicides mixed with insecticide that have been developed are safe for nursery box application even at sowing (Fig. 2). Panicle blast, however, is very difficult to control with a nursery box application, so foliar sprays and/ or into-water applications of granules are still required to control panicle blast. Although the one-shot application in nursery boxes became the mainstream in 2000s, there was a great change in the type of fungicides used (Fig. 3). In 2001, field resistance to MBI-Ds was reported when the use of MBI- Ds had expanded to around 250,000 ha, (estimated from Fig. 2 Symptoms of rice leaf blast, nursery box application of granular formulation of mixtures of a fungicide and an insecticide at sowing. a, b Rice leaf blast in paddy fields (Hirooka and Umetani 2004). c Apparatus for granule application in nursery box at sowing. d Granule application on bed soil from the hopper of the apparatus. e Nursery box with granules applied at sowing before covering with soil. f Rice seedlings after granule application at sowing

6 J Gen Plant Pathol (2013) 79: Fig. 3 Shipping volume of fungicides, according to mode of action, used for rice in Japan during the 2000s. MBI-D: melanin biosynthesis inhibitorsdehydratase, MBI-R: melanin biosynthesis inhibitorsreductase, QoI: Quinone outside inhibitors. (Data source: Japan Plant Protection Association) Shipping volume (t) 10,000 9,000 8,000 7,000 6,000 5,000 4,000 3,000 2,000 1, Year Host defense inducer MBI-D MBI-R Phospholipid QoI the shipping volume). MBI-Ds, rated by FRAC as having a medium risk for resistance development (Brent and Hollomon 2007), have been mostly replaced with host resistance inducers (probenazole and tiadinil) and MBI-Rs (tricyclazole, pyroquilon), which are rated as low risk based on their long-term use without any resistance problems. Since QoIs is rated as high fungicide risk and Magnaporthe is also rated as high pathogen risk, the use of orysastrobin, which has excellent efficacy against rice blast and sheath blight, then became prevalent. Details about countermeasures are described later. But reduced performance of orysastrobin was first reported in 2012 when the use of QoIs had expanded to about 200,000 ha, a presumable threshold for resistance development based on the fungicide resistance risk in M. oryzae. Several issues surrounding chemical control in Japan As mentioned earlier, fungicides with different modes of action are used to control the many important diseases such as scab, powdery mildews, gray mold of fruits and vegetables in Japan. Although many fungicides have been introduced to agricultural fields, farmers need effective control methods and appropriate implementation. The Research Committee of Evidence-Based Control (EBC) of the Phytopathological Society of Japan was established to use experimental evidence to develop a theory on disease control, and they hold workshops to extend the practice to a wider circle of people. The control of FHB in wheat and barley is extremely important because the fungus reduces grain quality and produces mycotoxins (Nakajima 2004). Thiophanatemethyl has been an effective fungicide to control FHB and mycotoxin accumulation (Nakajima 2004; Ueda and Yoshizawa 1988). Recently, optimal timings for the use of thiophanate-methyl on wheat and barley have been detailed (Yoshida and Nakajima 2012). When agricultural emissions of methyl bromide (MBr), an effective broad-spectrum fumigant against soilborne pathogens and pests, were implicated as a potentially significant contributor to stratospheric ozone depletion, developed countries mandated a complete ban of its use by 2005 as a precautionary measure and have needed to develop safe, effective alternative methods. In Japan, MBr was allowed in special cases for some vegetables, but that use was phased out by Alternatives to MBr developed by the National Agriculture and Food Research Organization in Japan as chemicals such as chloropicrin, physical control using solar heat, improved cultural management, and the introduction of resistant varieties (Nishi 2006). Regarding the regulations, a positive list system was implemented in 2006 to improve regulations to limit residual agricultural chemicals in foods. After implementation of the system, food import violations increased, greatly impacting countries that exported agricultural products to Japan (Tanaka and Uchimi 2007). Within Japan, farmers continued to comply with usage standards for agricultural chemicals and paid closer attention to preventing chemical drift during applications (Watanabe 2007). Chemical control of cereal diseases in Europe The great increase in cropping intensity in European cereal production in the 1960s and 1970s created a major market where practically none had existed. The remarkable ability

7 396 J Gen Plant Pathol (2013) 79: of new pathogens to adapt to intensively cultivated cereals has led to a large list of pathogens that can threaten these crops (Morton and Staub 2008). In Europe, cereals are classified as a high value crop, and chemical use is widespread, amounting to US$1.013 billion on cereals (Phillips McDougall 2011). Because a number of diseases have to be controlled at the same time on European cereals, the fungicides must have broad-spectrum of efficacy. Disease control on cereals begins with seed treatments. Seed treatments, used to control diseases such as bunt and smut caused by seed- and soil-borne pathogens, is fully consistent with integrated pest management (IPM), since fungicides provide control at extremely low rates and treatment of the seed restricts activity to a limited area around the seed (Allison 2002). DMIs and QoIs with strong systemic properties have been commercialized, but systemic activity is low when applied to seeds at recommended dose rates, thus strongly reducing the risk that fungal resistance will develop because air-borne pathogens are not targeted or pressurized (Suty-Heinze et al. 2004). Foliar sprays are applied generally two to three times per crop from just before jointing of plants to flowering. DMIs are intensively used, and mixed with fungicides having other modes of action such as QoIs to decrease the risk of resistance development and enhance the spectrum of efficacy (Dutzmann and Suty-Heinze 2004). The use of QoIs declined after field resistance developed in S. tritici, but has recently increased as part of a mixture with DMIs or new SDHIs, especially because of their greening effect that maximizes yield (Phillips McDougall 2011). FHB is a problem on wheat and barley in Europe also (Pirgozliev et al. 2003) and must also be factored into the chemical control strategy. Chemical control of soybean diseases in Brazil The area cropped with soybean in Brazil enlarged from 13 M ha in 1999 to 23.5 M ha in 2010, and fungicide sales increased from US$37 M in 1999 to US$900 M in 2010, presumably contributing to a yield increase from 2.4 to 2.9 t/ha (Phillips McDougall 2000, 2011). The good rainfall and high temperature is conducive to numerous fungal pathogens, which, if not controlled, may cause significant losses to a variety of crops including soybeans (Calegaro 2003). When an outbreak of Asian rust (Phakopsora pachyrhizi) reached the large soybean acreages in Brazil during 2000, fungicide use greatly increased. The broadspectrum fungicides, DMIs, QoIs, new SDHIs and thiophanates, are used to control soybean diseases. Fungicide resistance and countermeasures in Japan History and recent outbreak of fungicide resistance in Japan Fungicide resistance was first found in the field in 1971 when the efficacy of two antibiotics, polyoxin and kasugamycin, decreased respectively against black spot disease on Japanese pear (pathogen: Alternaria alternata Japanese pear pathotype) and blast disease on rice (M. oryzae) (Miura 1984; Nishimura et al. 1973). Since then, fungicide resistance has continued to cause problems, repeatedly decreasing fungicide efficacy on various crops (Table 2). Fungal strains resistant to benzimidazoles, which were common in the 1970s, are still widespread in Japan. Resistance to dicarboximides, Table 2 Field occurrence of fungicide resistance in Japan (major cases) Fungicide Polyoxin Kasugamycin Benzimidazoles Dicarboximides Phenylamides Demethylation inhibitors (DMIs) Fluazinum Quinone outside inhibitors (QoIs) Cyfulfenamid Scytalone dehydratase inhibitors (MBI-Ds) Succinate dehydrogenase inhibitors (SDHIs) Pathogen Alternaria alternata Japanese pear pathotype Magnaporthe oryzae Botrytis cinerea, Venturia nashicola, Monilinia fructicola, Gibberella fujikuroi, Cercospora kikuchii, Colletotrichum gloeosporioides B. cinerea, A. alternata Japanese pear pathotype Pseudoperonospora cubensis, Phytophthora infestans Podosphaera xanthii, Sphaerotheca aphanis var. aphanis, Mycovellosiella nattrasii, V. nashicola B. cinerea P. xanthii, P. cubensis, M. nattrasii, Corynespora cassiicola, B. cinerea, C. gloeosporioides, Passalora fulva, Pestalotiopsis longiseta, Plasmopara viticola, M. oryzae P. xanthii M. oryzae C. cassiicola, P. xanthii, B. cinerea, M. nattrasii

8 J Gen Plant Pathol (2013) 79: phenylamides, and DMI fungicides is also common. More recently, resistance to QoI, MBI-D and SDHI fungicides has been found as described next. QoI fungicide resistance It is well known that QoI fungicides are at very high risk for resistance to develop in the target pathogens. In fact, resistance in strains of fungal or oomycete pathogens to QoI fungicides caused a decrease in QoI performance in the field. Resistant strains have so far been detected in about 60 pathogen species worldwide including 22 species within Japan. A point mutation in the cytochrome b gene, causing the substitution of alanine for glycine at amino acid position 143, which is presumably involved in fungicidebinding affinity, is thought to be the major cause of high QoI resistance (Ishii 2012c). Most recently, however, another point mutation, leading to the substitution of phenylalanine for leucine, has been found at position 129 in two fungi, Passalora fulva (Watanabe 2011) and Pestalotiopsis longiseta (Yamada and Sonoda 2012). DNA-based molecular techniques such as PCR RFLP (Ishii et al. 2007) and real-time PCR (Banno et al. 2009) have been developed to identify QoI resistance rapidly. Although PCR RFLP is used frequently to diagnose resistance, the dynamics of the multi-copy mitochondrial cytochrome b gene, with the concomitant presence of mutated and wild-type genes in various ratios within the cells often causes difficulties in interpreting the results (Ishii 2009). Of major concern has been whether M. oryzae develops resistance to QoI fungicides in paddy fields, and molecular methods have been developed to diagnose such resistance (Wei et al. 2009). Intensive monitoring for resistance is ongoing because fungal isolates that are less sensitive to QoIs have already been detected (Nakamura et al. 2011). In 2012, field resistance was found in some areas in western Japan (Miyagawa and Fuji 2013). MBI-D fungicide resistance Nursery box treatments with the MBI-D fungicides carpropamid and diclocymet became a common cultural practice in many rice-growing areas because their efficacy in controlling rice blast had been long-lasting. However, in 2001, the efficacy of carpropamid against leaf blast was suddenly lost in Saga Prefecture, Kyushu (Yamaguchi 2003). Results from extensive studies indicated that resistant strains played a significant role in the decrease in efficacy (Sawada et al. 2004; Takagaki et al. 2004). It is very likely that the long-lasting efficacy, based on the persistent properties of the fungicide, has acted as a strong selection pressure against resistant strains, and they rapidly increased in fungal populations. As of 2011, resistant strains have been detected from 36 of 47 prefectures in Japan although the impact of resistance largely differs depending on the areas (Ishii 2012b). Molecular techniques such as PIRA-PCR (Kaku et al. 2003) and PCR-Luminex (Ishii et al. 2008) have been developed to identify resistant strains rapidly. Use of carpropamid and other MBI-D fungicides is stopped whenever wide range of distribution of resistant strains confirmed in an area. Results from monitoring tests suggest that resistant strains seem to be less fit to the environment once the selection pressure from the MBI-D fungicides is removed (Kimura 2006). SDHI fungicide resistance Many SDHIs are being developed around the world. However, resistance is developing against them also. For example, boscalid-resistant isolates of Corynespora cassiicola rapidly appeared (Miyamoto et al. 2009), and isolates resistant to penthiopyrad, which belongs to the same cross-resistance group as boscalid, have also been detected in the cucumber powdery mildew fungus (Miyamoto et al. 2010b). More recently, boscalid resistance has been found in Botrytis cinerea on strawberry (Suzuki et al. 2012) and Mycovellosiella nattrassii on eggplant (Okada et al. 2012). The molecular mechanism underlying boscalid resistance has been studied, and a point mutation in the sdhb gene in C. cassiicola is associated with both a very high and a high resistance to boscalid (Miyamoto et al. 2010a). The same mutation has also been detected from boscalidresistant isolates of P. xanthii and B. cinerea (Ishii et al. 2012; Miyamoto et al. 2010b). Interestingly, a novel SDHI fungicide fluopyram showed strong inhibitory activities not only against boscalid-sensitive but also highly boscalidresistant isolates, indicating that a slightly different site of action is involved for fluopyram than for boscalid and penthiopyrad (Ishii et al. 2011, 2012). DMI fungicide resistance DMIs have the biggest share of the world fungicide market. They have been used to control a variety of diseases on cereals, vegetables, fruit crops and others since the mid- 1980s in Japan. A decrease in fungal sensitivity to DMIs in general developed gradually. But now the efficacy of DMIs such as fenarimol and hexaconazole against scab, the most important disease of Japanese pear caused by Venturia nashicola, is inadequate (Ishii and Kikuhara 2007). When incomplete cross-resistance among DMIs exists, then difenoconazole should be mixed with other effective fungicides to control this disease.

9 398 J Gen Plant Pathol (2013) 79: Countermeasures Successive applications of fungicides that possess the same mode of action are well known to increase the likelihood that resistance will develop (Dekker 1982). Based on this theory and field experiences, alternative or mixed applications with one in a different group have been recommended. However, we already know that these conventional countermeasures cannot always stop the occurrence of fungicide resistance. After orysastrobin, a QoI fungicide, was marketed for rice, the Research Committee on Fungicide Resistance of the Phytopathological Society of Japan (PSJ Research Committee on Fungicide Resistance) prepared guidelines on how to use orysastrobin and other QoI fungicides that had already been on the market; only one application a per year is recommended, if necessary, and QoIs should be used as a nursery box treatment in alternation with other unrelated fungicides such as MBI-R fungicides or host defense inducers, e.g. probenazole every 2 3 years (So and Yamaguchi 2008). The same strategy is also recommended for MBI-D fungicides, if they are still effective. Unfortunately, however, QoI-resistant isolates of rice blast fungus have been detected recently from paddy fields where seeds had received the nursery box treatment with orysastrobin successively for the last several years. Guidelines on the use of QoIs and SDHIs in vegetables, fruit, and tea have also been released from PSJ Research Committee on Fungicide Resistance (Ishii 2012a). In 2009, the Committee issued a supplemental version of the laboratory manual (PSJ Research Committee on Fungicide Resistance 2009), which will be quite useful when testing fungicide sensitivity because the manual contains the majority of pathogens and fungicides with known problems. A database of literature relating to fungicide resistance reported in Japan accompanies the manual. Future subjects Disease management still relies largely on chemical control, but the occurrence of fungicide resistance may increase in the future because the choice of fungicides is often difficult when effective alternatives are lacking. Development and integration of disease management tools need to be accelerated not only to resolve the problem of fungicide resistance but also to alleviate public concerns about agricultural chemicals. Conclusions A re-registration process requires that agricultural chemicals satisfy the demand of regulatory authorities regarding low toxicity to humans and wildlife, low environmental impact, low residues in food and so on. The public and farmers also demand compatibility with IPM programs. These demands are the main criteria of agricultural chemical companies for deciding which fungicide to develop and commercialize, and the probability of discovery becomes lower. This change will then limit farmers choices for products (Knight et al. 1997). By contrast, the struggle against pathogens that limit food production, as shown in practical examples, will continue in the future. Our task is to maintain the available diversity in the mode of action groups of fungicides and implement countermeasures against fungicide resistance based on our cumulative knowledge. Acknowledgments The contributions of Japanese agricultural chemical companies to the discovery of fungicides referred in this review are listed alphabetically as follows: Kumiai (mepronil), Kumiai-Ihara (mepanipyrim, benthiavalicarb-isopropyl, pyribencarb), Kureha (fthalide, ipconazole, metconazole), Hokko (kasugamycin, imibenconazole), Ishihara (cyazofamid, fluazinam), Meiji Seika (probenazole), Mitsui (penthiopyrad), Nihon Bayer Agrochem/now Bayer CropScience (carpropamid), Nihon Nohyaku (isoprothiolane, flutolanil, fenoxanil, tiadinil), Nippon Soda (triflumizole, thiophanatemethyl), Nissan (amisulbrom), Sankyo/now Mitsui (simeconazole), Shionogi/now Bayer CropScience (metominostrobin), Sumitomo (procymidone, furametpyr, diclocymet), Takeda/now Sumitomo (ferimzone), Ube-Hokko (pefurazoate), Ube-Otsuka (oxpoconazole fumarate). Credits: H. Ishii wrote Fungicide resistance and countermeasures in Japan, and T. Hirooka wrote the rest. 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