Chemical Control of Septoria Leaf Blotch: history, biological performance, and molecular mode of action of DMI fungicides

Transcription

1 EPPO Workshop Azole fungicides and Septoria leaf blotch control, Rothamsted, UK, / 09 Chemical Control of Septoria Leaf Blotch: history, biological performance, and molecular mode of action of DMI fungicides Dr. Klaus Stenzel, Bayer CropScience AG

2 DMI brief definition Since the 1960 s several different chemical classes inhibiting the fungal sterol biosynthesis have been introduced to the market - Sterol Biosynthesis Inhibitors (SBI s) The classes were grouped by their common mode of action and crossresistance behaviour Fungicides inhibiting the C-14 demethylase in the sterol biosynthesis are the most relevant group within the SBI group - C-14 demethylase inhibitors ( DMI fungicides, DMI s ) EPPO Dec 2010 K.Stenzel Slide 2

3 The sterol biosynthesis source of modes of action squalene-epoxidase epoxisqualene-cyclase HO DMI s C-14-demethylase HO amines HO ergosterol 14 -reductase HO hydroxyanilides amines C3-ketoreductase HO C3-ketoreductase HO 8 7 -isomerase HO EPPO Dec 2010 K.Stenzel Slide 3

4 Different chemical classes of SBI s C 14 -demethylase (DMI s) 8 7 isomerase + 14 reductase C 3 ketoreductase Triazoles Imidazoles Piperazines Pyrimidines Pyridines Spiroketalamines Morpholines Piperidines Hydroxyanilides Prochloraz Imazalil etc. Fenarimol Nuarimol Fenpropidin Triadimefon Triadimenol Propiconazole Tebuconazole Cyproconazole Flusilazole Difenoconazole Epoxiconazole Metconazole Prothioconazole etc. Triforine Pirifenox Dodemorph Tridemorph Fenpropimorph Spiroxamine Fenhexamid 35 DMI fungicides have been launched largest SBI group EPPO Dec 2010 K.Stenzel Slide 4

5 Grouping of fungicides by FRAC DMI 33.5 bn * 2.2 bn in 2009* Other SBI 3.6 bn * 0.1 bn 2009 * Strobilurines 9.9 bn * 1.3 bn in 2009* * Sales. Source: Agrowin DMI fungicides are the most relevant fungicide group ~ 1/3 of fungicide market EPPO Dec 2010 K.Stenzel Slide 5

6 Launch of new fungicidal modes of action 50 accum. number year Why are the SBI s such an extraordinary success story? EPPO Dec 2010 K.Stenzel Slide 6

7 DMI the beginning In the 1960 s only fungicides available showing - limited spectrum of activity - protective action - no systemic activity Crop protection insufficient in important crop segments, e.g. cereals Need for new solutions Discovery of the imidazoles (Janssen Pharmaceutica, NL) first DMI s reaching the market - starting point for the development of antimycotics and fungicides 1976 first systemic triazoles launched (triadimefon and triadimenol, Bayer AG, D) a breakthrough and starting point of the triazole success story EPPO Dec 2010 K.Stenzel Slide 7

8 Market launch of members of the different chemical DMI groups cumulated no. of launched compounds triazoles imidazoles piperazines pyridines pyrimidines imidazoles triazoles Continuous market introduction of new DMI compounds, mainly triazoles EPPO Dec 2010 K.Stenzel Slide 8

9 The success story of DMI s in agriculture m sales DMI Amines Source:Agrowin Essential role of triazoles in crop protection Source: AgroWin 2010 EPPO Dec 2010 K.Stenzel Slide 9

10 Year of introduction and market success of individual triazoles m peak turnover (incl. 2009) Triadimefon Propiconazole Triadimenol Bitertanol Cyproconazole Flusilazole Tebuconazole Flutriafol Myclobutanil Tetraconazole Difenoconazole Penconazole Triticonazole Diniconazole Fenbuconazole : Bromuconazole 2: Ipconazole Epoxiconazole Metconazole Fluquinconazole 3: Azaconazole 4: Imibenconazole Prothioconazole Simeconazole Oxpoconazole BASF BCS Dow DuPont Hokko Isagro Janssen Kureha Sankyo Sumitomo Syngenta UBE Launch year Source:Agrowin 2010 EPPO Dec 2010 K.Stenzel Slide 10

11 DMI reasons for success potentially broad spectrum of activity covering most pathogens belonging to the Ascomycetes and Basidiomycetes broad chemical variability resulting in broad variability in biological properties systemic behaviour pronounced curative activity use as spray, seed treatment, soil treatment good plant compatibility, usable side effects on plant physiology favorable toxicological and ecotoxicological profile shifting type of resistance allowing effective resistance management Only a favorable combination makes a relevant product for agriculture EPPO Dec 2010 K.Stenzel Slide 11

12 The efficacy in new diseases Asian soybean rust Phakopsora pachyrhizi introduction of a non-endemic disease and epidemiological spread over a continent untreated triazole Wheat stem rust Puccinia graminis Ug 99 genetic plant resistance broken: full susceptibility high disease pressure when no fungicides are applied efficacy of azoles confirmed Broad spectrum activity protecting against new threats for agriculture EPPO Dec 2010 K.Stenzel Slide 12

13 Relevance of SBI s for crop segments 2007 cer eals f ruit s, veg et ab les and g rap es so yb ean rice % of SBI sales OSR Data Source: Agrowin Broad spectrum with focus on cereals EPPO Dec 2010 K.Stenzel Slide 13

14 The dynamcis in triazoles, exemplified by main products in the main market cereals 2004 Prothioconazole BCS broad spectrum with strenghts against Septoria tritici and Fusarium (Mycotoxins) 1989 Tebuconazole BCS Broad spectrum including Fusarium ear blight (mycotoxins) 1976/80 Triadimefon BCS Rust and powdery mildew strengths 1993 Epoxiconazole BASF broad spectrum with strength against Septoria tritici (new lead pathogen in cereals) 1979 Propiconazole SYN broader spectrum of activity than Triadimefon. First shifts to leaf spot diseases (Helminthosporium) Multiple generations with improved quality, following dynamics in the pathogen spectrum EPPO Dec 2010 K.Stenzel Slide 14

15 Change in key pathogens in wheat in EU relative importance high Septoria nodorum Puccinia Septoria tritici low Powdery Mildew triforine triadimefon non-triazole DMI s propiconazole triazole DMI s tebuconazole cyproconazole epoxiconazole prothioconazole Source: K.-H. Kuck EPPO Dec 2010 K.Stenzel Slide 15

16 DMI the mode of action discovery Identification of ergosterol as an essential component in fungal cell membranes (1953, 1964, 1968) Increasing knowledge about synthesis, composition and function of sterols in fungal cells in the late 1960 s and the early 1970 s biochemical investigations by the teams of Ragsdale and Sisler (1973), Kato (1974), Ragsdale (1975) and Buchenauer (1977) showed that a group of chemicals inhibit the demethylation of lanosterol at position 14 in the fungal sterol biosynthesis the DMI s all DMI s are causing typical morphological changes of fungal hyphae EPPO Dec 2010 K.Stenzel Slide 16

17 CYP51 the target of DMI fungicides Trypanosoma brucei in complex with posaconazole (2 conformations) Source: Proteindatabase pdb no. 2X2N Several crystal structures of cyp51 available none from a fungus Due to additional amino acids in fungi precise modelling of some mutations impossible EPPO Dec 2010 K.Stenzel Slide 17

18 Differences in time pattern of sterol biosynthesis in fungi ergosterol and all C-4 desmethylsteroles ergosterol and all C-4 desmethylsteroles 200 c/h Phakopsora: 3 h germination 600 c/h Phakopsora: 30 h germination 200 c/h 600 c/h Phakopsora: 6 h germination Phakopsora: 48 h germination 600 c/h start front Botrytis: 6 h germination start front Incubation with 14 C-acetate during the whole germination period Knowledge about time pattern of sterol biosynthesis can be crucial EPPO Dec 2010 K.Stenzel Slide 18

19 Abnormal sterol distribution leads to malformations malformations in the intracellular membrane system and the cell wall of fungi hyphae become abnormally swollen and branching can be seen hyphal cell wall breaks and is covered with extruded material Septoria tritici untreated Consequences reduced penetration and establishment of infection reduced spread within the plant reduced reproduction and further growth treated with triazole EPPO Dec 2010 K.Stenzel Slide 19

20 Effects of azole treatment on early phase of Septoria tritici untreated untreated treated treated ** 24 hpi, protective treatment (1 d) with triazole* * prothioconazole EPPO Dec 2010 K.Stenzel Slide 20

21 Effects on early phases of powdery mildew on wheat 96 hpi, protective treatment with triazole* * prothioconazole EPPO Dec 2010 K.Stenzel Slide 21

22 Systemicity of azoles another key for success All currently known DMI s are at least partially mobile in the apoplast of the plants leading to re-distribution of the active ingredient in the plant penetration into the plant reduces risk of interference with adverse weather conditions curative effects based on systemicity Broad variability of systemicity in dependance on the chemical structure and the corresponding phys-chem properties Locosystemic activity can also lead to curative activity EPPO Dec 2010 K.Stenzel Slide 22

23 Systemicity of azoles example for distribution in cereals 14 C-Tebuconazole 14 C-Prothioconazole a.i. concentration high low 1d 7d 1d 7d Droplet application (10 µl / 2 kbq / wheat leaf / 6 hours) Quick systemic availability focus on curative activity Slow distribution - focus on residual activity EPPO Dec 2010 K.Stenzel Slide 23

24 Biological performance I Efficacy of azoles against wheat diseases azole powdery mildew Septoria tritici Helminthosporium triticirepentis Fusarium graminearum cpyroconazole epoxiconazole flusilazole metconazole propiconazole prothioconazole tebuconazole tetraconazole not registered low efficacy medium efficacy good efficacy Source: Arvalis 2009 Triazoles cover a broad spectrum of diseases in cereals EPPO Dec 2010 K.Stenzel Slide 24

25 Biological performance I Efficacy of azoles against wheat diseases Source: HGCA, The wheat disease management guide 2010, Spring 2010; Triazole molecules - top performer covering a broad spectrum of cereal diseases EPPO Dec 2010 K.Stenzel Slide 25

26 Biological performance II azoles supporting high volume and high quality yields Yield (wheat) mycotoxin content (wheat) 100 (dt/ha) 1250 DON (µg/kg) 95 95,8 95, , , BBCH31/32 und BBCH39/ UC UC(T3) Triazole 1 Triazole 2 0 UC UC(T3) Triazole 1 Triazole 2 Trials from 2005 and 2006 in EU. Final treatment at GS (T3): UC untreated control, UC (T3) untreated at T3 only; Triazole 1 Triazole mixture, Triazole 2 - triazole & strobilurine Yield increase and reduction of mycotoxin content full disease management EPPO Dec 2010 K.Stenzel Slide 26

27 Resistance mechanisms for DMI s Four major mechanisms that may operate They are unrelated but may act simultaneously increased efflux (overexpression of efflux-pumps) altered target site (mutations in cyp 51 gene) decreased demand for target-site product target-site overproduction (overexpression of cyp 51) (Brent and Hollomon, FRAC Monograph No. 1, ed. 2007) Multigenic resistance mechanism leading to gradual development of resistance EPPO Dec 2010 K.Stenzel Slide 27

28 Shifting - resistance type of DMI s 7 field rate Frequency selection fitness 0 high sensitivity low continuous or stepwise selection and loss of field efficacy: shifting type rapid back-shifting possible resistance factors mostly low to moderate compensation by more active molecules possible visit ww.frac.info for further information Effective resistance management contributed to the overall stable situation EPPO Dec 2010 K.Stenzel Slide 28

29 Development of sensitivity values: Wheat Powdery Mildew / Tebuconazole MRF UK F D 20 MRF: Mean Resistance Factor Data: Dr. F.G. Felsenstein Typical fluctuations / variations over the years indicating a stable situation year EPPO Dec 2010 K.Stenzel Slide 29

30 Summary DMI s were discovered in the 60 s, first systemic DMI s were launched 1976 the mode of action was identified in the 70 s triazoles most successful chemical class with 25 market compounds key success factors in chemical diversity and biological properties protective, curative and systemic activity broad spectrum activity shifting type of resistance triazoles are an indispensable and valuable tool in an integrated crop management careful and responsible use of triazoles necessary to preserve this tool to ensure future usability to ensure efficient crop protection tackling the growing demand for food and feed production in agriculture DMI s the chemical fungicide class with the most success and high value in modern crop protection with continously growing needs and opportunities EPPO Dec 2010 K.Stenzel Slide 30

31 Thank you very much for your kind attention.