Wheat is the most important cereal crop in the world. It occupies 17% of the cultivated land and is the main source of food for 35% of the world population. InIran, wheat is the most important agricultural crop and bread as its main product provides over 50% of daily consumed calories.The ascomycetousfungus Mycosphaerella graminicola(Fuckel) J. Schroeter isthe causal agent of septoria tritici leaf blotch disease of wheat.The fungus has gradually emerged as one of the most damagingfoliarpathogensespeciallyin areas with high rainfall during the growing season.Septoria tritici leaf blotch diseaseis mainly managed by usingresistant cultivars, cultural practices, and chemical control.Extensive application of different classes of fungicidesto control the disease has imposed selection pressure on this pathogen leading to evolutionof fungicide-resistant strains.The objective of this thesis was the analysis of major facilitator superfamily (MFS) and ATP-binding cassette (ABC) drug efflux transporters of M. graminicola for their role in fungicide sensitivity, multidrug resistance (MDR) development and virulence on wheat. The thesis also describes a novel type of ABC transporter with a role in iron homeostasis. Inhibitors of drug transporters that function as virulence factors may act as indirect disease control agents and therefore, the potency of medical modulators of ABC drug transporters to control septoria leaf blotch on wheat seedlings was investigated.Chapter 1 presents a general overview on the global importance of wheat, septoria leaf blotch, M. graminicola , and disease management. Special attention is given to chemical control of the disease, fungicide resistance, and the role of drug transporters in fungicide sensitivity and resistance.Chapter 2 gives a review on MFS transporters with special emphasis on drug transporters and their relevance in plant pathogenic fungi. This chapter provides an overview of common characteristics of MFS transporters, including theirclassification, physical characteristics, and themechanisms of transport. Furthermore, the role of several MFS transporters from plant pathogenic fungi in secretion of various types of antifungal compounds, MDR and virulence are reviewed. Finally, the impact of fungal MFS drug transporters on fungicide baseline sensitivity, MDR, and drug discovery is discussed.The chapters 3>and 4 focus on the identification and functional analysis of theMFS transporter gene MgMfs1 , the first MFS transporter gene cloned from M. graminicola with high homology to fungal MFS transporters within the DHA2 family, involved in mycotoxin secretion and MDR. The results described in chapter 3 indicate that MgMfs1 is not involved in virulence on wheat. However, heterologous expression of this gene in yeast and the phenotypic characterization of MgMfs1 disruption mutants of M. graminicola demonstrate that in vitro MgMfs1 can act as a very potent multidrug transporter, capable totransport a wide range of substrates such as fungal toxins, plant metabolites, and fungicides, particularly strobilurins. In Chapter 4, it is demonstrated that MgMfs1plays a significant role in both in vitro and in plantasensitivity ofM. graminicola to thestrobilurin fungicide trifloxystrobin. The efflux of strobilurin fungicides inMgMfs1 disruption mutants is reduced, and in disease control experiments on wheat seedlings these disruption mutants exhibit an increased sensitivity to trifloxystrobin. Chapter 4 also demonstrates that, besides the dominant G143A target site mutation in the cytochrome b gene, overexpression of MgMfs1 may act as an additional protection mechanism in strobilurin-resistant field strains. MgMfs1 overexpression is probably required for proper maintenance of membrane functioning and normal fitness of these strains in the presence of strobilurins.Chapter 5 describes the molecular cloning and functional characterization of MgAtr7, an ABC transporter gene withhigh homology to fungal ABC transporters involved in azole sensitivity that seems to be unique for M. graminicola and Fusarium graminearum . The encoded protein MgAtr7 is a novelhybrid type of ABC transporterwith the [NBF-TM] 2 configuration which contains a motif characteristic for a dityrosine / pyoverdine biosynthesis protein at the N-terminus, and is the first member of a new class of fungal ABC transporters harboring both a transporter and a biosynthetic moiety. Functional analyses revealed that the gene is involved neither in fungicide sensitivity nor in virulence on wheat, but functions in maintenance of iron homeostasis.Chapter 6 describes the ability of medical drugs known to modulate the activity of ABC transporters, to potentiate the activity of the azole fungicide cyproconazole against in vitro growth of M. graminicola and to control disease development of the pathogen on wheat seedlings. It is shown that some of these compounds can synergize cyproconazole activity in vitro and inhibit efflux activity of the fungicide from fungal cells. However, synergistic interactions between the modulators and cyproconazole were not observed in planta . Some of the compounds have virtually no toxic activity to M. graminicolain vitro , but do show a significant disease control activity on wheat seedlings in preventive and curative foliar spray experiments. The results suggest that these compounds have an indirect disease control activity based on modulation of fungal ABC transporters essential for virulence. Such modulators may constitute a new class of disease control agents. , the function of the ABC transporter MgAtr7 in iron-siderophore transport, and the potential of modulators of ABC transporters to act as lead products in the development of disease control agents.In conclusion, the data presented in this thesis show that the MFS drug transporter MgMfs1 from M. graminicola plays an important role in fungicide sensitivity and resistance, specifically in relation to the strobilurin fungicides. A new type of ABC drug transporter with a new function in iron homeostasis was discovered. In addition, we demonstrated that medical drugs known as modulators of ABC transporters can have an indirect disease control activity and may constitute a new class of disease control agents.