Respiration Inhibitors: Complex II

  • Gerd Stammler
  • Antje Wolf
  • Alice Glaettli
  • Kristin Klappach


The succinate dehydrogenase inhibitors (SDHIs) are a highly attractive group of fungicides with regard to their history of use, chemical innovations, and spectrum of targeted diseases. They are the most modern, broadly effective fungicide group available to farmers for their disease control programs. As the group name indicates, the mode of action of SDHIs is the inhibition of succinate dehydrogenase in the respiration chain. Along with the broadening of their disease control palette, the structural complexity of the SDHIs has been increased. Nevertheless, the currently known SDHIs share common chemical features necessary for fungicidal activity, suggesting a very similar binding to the target as demonstrated here by three-dimensional alignment and computational docking experiments. Different target site mutations have been found in laboratory mutants and field isolates of various fungal species. Modeling studies with different target site mutations indicated that some of the observed target alterations conferring resistance to SDHIs have a direct impact on the binding behavior of SDHIs, whereas other mutations influence SDHI binding by long-range structural rearrangement in the transmembrane region of complex II. A diverse picture is seen regarding the effects of these mutations on the sensitivity toward various SDHIs in various pathogens and thus regarding cross-resistance. Some mutations cause a loss of sensitivity to all currently commercialized SDHIs, but there are also mutations where no complete cross-resistance can be found. Therefore, it can be stated that cross-resistance between SDHIs exists in general, but phenotypically exceptions are observed.


Binding Carboxamides Complex II Fungicides Resistance SDHI Succinate dehydrogenase Target site mutation 


  1. Abiko K, Kishi K, Yoshioka A (1977) Occurrence of oxycarboxin-tolerant isolates of Puccinia horiana P. Hennings in Japan. Ann Phytopathol Soc Jpn 43:145–150CrossRefGoogle Scholar
  2. Ackrell BAC, Kearney EB, Coles CJ, Singer TP, Beinert H, Wan YP, Folkers K (1977) Kinetics of the reoxidation of succinate dehydrogenase. Arch Biochem Biophys 182:107–117CrossRefPubMedGoogle Scholar
  3. Anderson RF, Hille R, Shinde SS, Cecchini G (2005) Electron transfer within complex II – succinate: ubiquinone oxidoreductase of Escherichia coli. J Biol Chem 280:33331–33337CrossRefPubMedGoogle Scholar
  4. Avenot HF, Michaelidis TJ (2007) Resistance to boscalid fungicide in Alternaria alternata isolates from pistachio in California. Plant Dis 91:1345–1350CrossRefGoogle Scholar
  5. Avenot HF, Thomas A, Gitaitis RD, Langston DB, Stevenson KL (2012) Molecular characterization of boscalid- and penthiopyrad-resistant isolates of Didymella bryoniae and assessment of their sensitivity to fluopyram. Pest Manag Sci 68:645–651CrossRefPubMedGoogle Scholar
  6. Ben-Yephet Y, Dinoor A, Henis Y (1975) The physiological basis of carboxin sensitivity and tolerance in Ustilago hordei. Phytopathology 65:936–942CrossRefGoogle Scholar
  7. Billard A, Fillinger S, Leroux P, Lachaise H, Beffa R, Debieu D (2012) Strong resistance to the fungicide fenhexamid entails a fitness cost in Botrytis cinerea, as shown by comparisons of isogenic strains. Pest Manag Sci 68:684–691CrossRefPubMedGoogle Scholar
  8. Cecchini G (2003) Function and structure of complex II of the respiratory chain. Annu Rev Biochem 72:77–109CrossRefPubMedGoogle Scholar
  9. Dokmanic I, Sikic M, Tomic S (2007) Metals in proteins: correlation between the metal-ion type, coordination number and the amino-acid residues involved in the coordination. Acta Crystallogr D64:257–263Google Scholar
  10. Fernandez-Ortuno D, Chen F, Schnabel G (2012) Resistance to pyraclostrobin and boscalid in Botrytis cinerea isolates from strawberry fields in the Carolinas. Plant Dis 96:1198–1203CrossRefGoogle Scholar
  11. Fraaije BA, Bayon C, Atkins S, Cools HJ, Lucas JH, Fraaije MW (2012) Risk assessment studies on succinate dehydrogenase inhibitors, the new weapons in the battle to control Septoria leaf blotch in wheat. Mol Plant Pathol 13:263–275CrossRefPubMedGoogle Scholar
  12. Fraile A, Alonso A, Sagasta EM (1986) Some characteristics of Botrytis cinerea isolates tolerant to procymidone. Plant Pathol 35:82–85CrossRefGoogle Scholar
  13. Genet JL, Jaworska G, Deparis F (2006) Effect of dose rate and mixtures of fungicides on selection for QoI resistance in populations of Plasmopara viticola. Pest Manag Sci 62:188–194CrossRefPubMedGoogle Scholar
  14. Georgopoulos SG, Alexandri E, Chrysayi M (1972) Genetic evidence for the action of oxathiin and thiazole derivatives on the succinic dehydrogenase system of Ustilago maydis mitochondria. J Bacteriol 110:809–817PubMedCentralPubMedGoogle Scholar
  15. Georgopoulos SG, Chrysayi M, White GA (1975) Carboxin resistance in the haploid, the heterozygous diploid, and the plant-parasitic dicaryotic phase of Ustilago maydis. Pestic Biochem Physiol 5:543–551CrossRefGoogle Scholar
  16. Glaettli A, Stammler G, Schlehuber S (2009) Mutations in the target proteins of succinate-dehydrogenase inhibitors (SDHI) and 14α-demethylase inhibitors (DMI) conferring changes in the sensitivity – structural insights from molecular modelling. In: 9th international conference on plant diseases, Tours, France, pp 670–681Google Scholar
  17. Horsefield R, Iwata S, Byrne B (2004) Complex II from a structural perspective. Curr Protein Pept Sci 5:107–118CrossRefPubMedGoogle Scholar
  18. Horsefield R, Yankovskaya V, Sexton G, Whittingham W, Shiomi K, Omura S, Byrne B, Checchini G, Iwata S (2006) Structural and computational analysis of the quinone-binding site of complex II (succinate-ubiquinone oxidoreductase). J Biol Chem 281:7309–7316CrossRefPubMedGoogle Scholar
  19. Huang L, Sun G, Cobessi D, Wang AC, Shen JT, Tung EY, Anderson VE, Berry EA (2006) 3-Nitropropionic acid is a suicide inhibitor of mitochondrial respiration that, upon oxidation by complex II, forms a covalent adduct with a catalytic base arginine in the active site of the enzyme. J Biol Chem 281:5965–5972PubMedCentralCrossRefPubMedGoogle Scholar
  20. Ishii H, Miyamoto T, Ushio S, Kakishima M (2011) Lack of cross-resistance to a novel succinate dehydrogenase inhibitor, fluopyram, in highly boscalid-resistant isolates of Corynespora cassiicola and Podosphaera xanthii. Pest Manag Sci 67:474–482CrossRefPubMedGoogle Scholar
  21. Ito Y, Muraguchi H, Seshime Y, Oita S, Yanagi SO (2004) Flutolanil and carboxin resistance in Coprinus cinereus conferred by a mutation in the cytochrome b560 subunit of succinate dehydrogenase complex (Complex II). Mol Genet Genomics 272:328–335CrossRefPubMedGoogle Scholar
  22. Johnson KB, Sawyer TL, Powelson ML (1994) Frequency of benzimidazole- and dicarboximide-resistant strains of Botrytis cinerea in western Oregon small fruit and snap bean plantings. Plant Dis 78:572–577CrossRefGoogle Scholar
  23. Keon JP, White GA, Hargreaves JA (1991) Isolation, characterization and sequence of a gene conferring resistance to the systemic fungicide carboxin from the maize smut pathogen, Ustilago nuda. Curr Genet 19:475–481CrossRefPubMedGoogle Scholar
  24. Kuhn PJ (1984) Mode of action of carboxamides. Br Mycol Soc Sym Ser 9:155–183Google Scholar
  25. Leroux P, Berthier G (1988) Resistance to carboxin and fenfuram in Ustilago nuda (Jens) Rostr, the causal agent of barley loose smut. Crop Prot 7:16–19CrossRefGoogle Scholar
  26. Li J, Zhou M, Li H, Chen C, Wang J, Zhang Y (2006) A study on the molecular mechanism of resistance to amicarthiazol in Xanthomonas campestris pv. citri. Pest Manag Sci 62:440–445CrossRefPubMedGoogle Scholar
  27. Linck H (2013) Method development for the efficacy evaluation of biological control agents against Botrytis cinerea. Master thesis, University HohenheimGoogle Scholar
  28. Maklashina E, Rothery RA, Weiner JH, Cecchini G (2001) Retention of heme in axial ligand mutants of succinate-ubiquinone oxidoreductase (complex II) form Escherichia coli. J Biol Chem 276:18968–18976CrossRefPubMedGoogle Scholar
  29. Maklashina E, Rajagukguk S, McIntire WS, Cecchini G (2010) Mutation of the heme axial ligand of Escherichia coli succinate-quinone reductase: Implications for heme ligation in mitochondrial complex II from yeast. Biochim Biophys Acta 1797:747–754PubMedCentralCrossRefPubMedGoogle Scholar
  30. Mathre DE (1970) Mode of action of oxathiin systemic fungicides. I. Effect of carboxin and oxycarboxin on the general metabolism of several basidiomycetes. Phytopathology 60:1464–1469CrossRefGoogle Scholar
  31. Mathre DE (1971) Mode of action of oxathiin systemic fungicides. III. Effect on mitochondrial activities. Pestic Biochem Physiol 1:216–224CrossRefGoogle Scholar
  32. Matsson M, Hederstedt L (2001) The carboxin-binding site on Paracoccus denitrificans succinate: quinone reductase identified by mutations. J Bioenerg Biomembr 33:99–105CrossRefPubMedGoogle Scholar
  33. Matsson M, Ackrell BAC, Cochran B, Hederstedt L (1998) Carboxin resistance in Paracoccus denitrificans conferred by a mutation in the membrane anchor of succinate: quinone reductase (complex II). Arch Mircobiol 170:27–37Google Scholar
  34. Miles TD, Miles LA, Fairchild KL, Wharton PS (2013) Screening and characterization of resistance to succinate dehydrogenase inhibitors in Alternaria solani. Plant Pathol 53:155–164Google Scholar
  35. Miyamoto T, Ishii H, Seko T, Kobori S, Tomita Y (2009) Occurrence of Corynespora cassiicola isolates resistant to boscalid on cucumber in Ibaraki Prefecture, Japan. Plant Pathol 58:1144–1151CrossRefGoogle Scholar
  36. Miyamoto T, Ishii H, Stammler G, Koch A, Ogawara T, Tomita T, Fountaine J, Ushio T, Seko T, Kobori S (2010a) Distribution and molecular characterization of Corynespora cassiicola strains resistant to boscalid. Plant Pathol 59:873–881CrossRefGoogle Scholar
  37. Miyamoto T, Ishii H, Tomita T (2010b) Occurrence of boscalid resistance in cucumber powdery mildew in Japan and molecular characterization of the iron-sulfur protein of succinate dehydrogenase of the causal fungus. J Gen Plant Pathol 76:261–267CrossRefGoogle Scholar
  38. Nakamura K, Yamaki M, Sarada M, Nakayama S, Vibat CRT, Gennis RB, Nakayashiki T, Inokuchi H, Kojima S (1996) Two hydrophobic subunits are essential for the heme b ligation and functional assembly of complex II (succinate-ubiquinone oxidoreductase) from Escherichia coli. J Biol Chem 271:521–527CrossRefPubMedGoogle Scholar
  39. Oyedotun KS, Sit CS, Lemire BD (2007) The Saccharomyces cerevisiae succinate dehydrogenase does not require heme for ubiquinone reduction. Biochim Biophys Acta 1767:1436–1445CrossRefPubMedGoogle Scholar
  40. Ragsdale NN, Sisler HD (1970) Metabolic effects related to fungitoxicity of carboxin. Phytopathology 60:1422–1427CrossRefPubMedGoogle Scholar
  41. Ramsay RR, Ackrell BAC, Coles CJ, Singer TP, White GA, Thorn GD (1981) Reaction site of carboxanilides and of thenoyltrifluoroacetone in complex II. Proc Natl Acad Sci U S A 78:825–828PubMedCentralCrossRefPubMedGoogle Scholar
  42. Raposo R, Gomez V, Urrutia T, Melgarejo P (2000) Fitness of Botrytis cinerea associated with dicarboximide resistance. Phytopathology 90:1246–1249CrossRefPubMedGoogle Scholar
  43. Ruprecht J, Yankovskaya V, Maklashina E, Iwata S, Cecchini G (2009) Structure of Escherichia coli succinate:quinone oxidoreductase with an occupied and empty quinone-binding site. J Biol Chem 284:29836–29846PubMedCentralCrossRefPubMedGoogle Scholar
  44. Scalliet G, Bowler J, Luksch T, Kirchhofer-Allan L, Steinhauer D, Ward K, Niklaus M, Verras A, Csukai M, Daina A (2012) Mutagenesis and functional studies with succinate dehydrogenase inhibitors in the wheat pathogen Mycosphaerella graminicola. PLoS One 7, e35429PubMedCentralCrossRefPubMedGoogle Scholar
  45. Skinner W, Bailey A, Renwick A, Keon J, Gurr S, Hargreaves J (1998) A single amino-acid substitution in the iron-sulphur protein subunit of succinate dehydrogenase determines resistance to carboxin in Mycosphaerella graminicola. Curr Genet 34:393–398CrossRefPubMedGoogle Scholar
  46. Stammler G, Brix HD, Glaettli A, Semar M, Schoefl U (2007) Biological properties of the carboxamide boscalid including recent studies on its mode of action. In: Proceedings of BCPC XVI international plant protection congress, Alton. British Crop Protection Council Publications, Hampshire, pp 16–21Google Scholar
  47. Stammler G, Brix HD, Nave B, Gold R, Schoefl U (2008) Studies on the biological performance of boscalid and its mode of action. In: Dehne HW et al (eds) Modern fungicides and antifungal compounds V. 15th international Reinhardsbrunn symposium 2007, pp 45–51Google Scholar
  48. Stammler G, Glaettli A, Koch A (2010) Mutations in the target protein conferring resistance to SDHI fungicides. In: Dehne HW et al (eds) Modern fungicides and antifungal compounds V. 16th international Reinhardsbrunn symposium 2010, pp 195–198Google Scholar
  49. Stammler G, Rehfus A, Prochnow J, Bryson R, Strobel D (2014) New findings on the development of insensitive isolates of Pyrenophora teres towards SDHI fungicides. Julius-Kühn-Archiv 447:568Google Scholar
  50. Tran QM, Rothery RA, Maklashina E, Cecchini G, Weiner JH (2007) Escherichia coli succinate dehydrogenase variant lacking the heme b. Proc Natl Acad Sci U S A 104:18007–18012PubMedCentralCrossRefPubMedGoogle Scholar
  51. Ulrich JT, Mathre DE (1972) Mode of action of oxathiin systemic fungicides. V. Effect on electron transport system of Ustilago maydis and Saccharomyces cerevisiae. J Bacteriol 110:628–632PubMedCentralPubMedGoogle Scholar
  52. Veloukas T, Leroch M, Hahn M, Karaoglanidis GS (2011) Detection and molecular characterization of boscalid-resistant Botrytis cinerea isolates from strawberry. Plant Dis 95:1302–1307CrossRefGoogle Scholar
  53. Veloukas T, Markoglou AN, Karaoglanidis GS (2013) Differential effect of SdhB gene mutations on the sensitivity to SDHI fungicides in Botrytis cinerea. Plant Dis 97:118–122CrossRefGoogle Scholar
  54. Veloukas T, Kalogeropoulou P, Markoglou A, Karaoglanidis G (2014) Fitness and competitive ability of Botrytis cinerea field-isolates with dual resistance to SDHI and QoI fungicides, associated with several sdhB and the cytb G143A mutations. Phytopathology 104:347–356CrossRefPubMedGoogle Scholar
  55. von Schmeling B, Kulka G (1966) Systemic fungicidal activity of 1,4-oxathiin derivatives. Science 152:659–660CrossRefPubMedGoogle Scholar
  56. Yankovskaya V, Horsefield R, Törnroth S, Luna-Chavez C, Miyoshi H, Léger C, Byrne B, Ceccini G, Iwata S (2003) Architecture of succinate dehydrogenase and reactive oxygen species generation. Science 299:700–704CrossRefPubMedGoogle Scholar

Copyright information

© Springer Japan 2015

Authors and Affiliations

  • Gerd Stammler
    • 1
  • Antje Wolf
    • 2
  • Alice Glaettli
    • 2
  • Kristin Klappach
    • 1
  1. 1.Agricultural CenterBASF SELimburgerhofGermany
  2. 2.Specialty Chemicals ResearchBASF SELudwigshafenGermany

Personalised recommendations