2. Fungicide resistance

Drug resistance is known as a serious problem for the medical treatment of infections by bacteria, parasites, viruses. In agriculture, a similar situation is emerging, because rising frequencies of fungicide resistance increasingly threaten the control of major fungal diseases. Botrytis cinerea is known as a high risk organism that can rapidly develop fungicide resistance in the field. While the major fungicide resistance mechanism in fungi is target site alteration, efflux-based, so-called multidrug resistance (MDR), conferring low to intermediate resistance levels against different fungicides, can also be an important mechanism of Botrytis under field conditions (Hahn and Leroch, 2015). Two major types of MDR, involving overexpression of different drug efflux transporters, have been discovered and elucidated on the molecular level (Kretschmer et al., 2009; Hahn and Leroch, 2015). MDR1 is widely distributed in wine and strawberry fields in Europe and the Southeastern USA and of practical relevance, because it is the only resistance mechanism observed in the field against the fungicide fludioxonil. MDR1 is caused by gain-of-function mutations in a gene encoding the transcription factor Mrr1, which leads to permanent activation of its target genes and overexpression of the ABC transporter encoding gene atrB (Kretschmer et al., 2009; Fig. 1). A stronger variant of MDR1, called MDR1h, resulting in increased levels of partial resistance to fludioxonil and cyprodil, was found to be correlated with the ∆L497 mutation in mrr1 (Leroch et al., 2013).

Fig. 1. Mutations and proposed mechanisms of <i>artB </i>activation in <i>B. cinerea </i>MDR1 strains. A: MDR1(h)-related gain-of-function mutations (amino acid exchanges) in the transcription factor Mrr1. Only the ΔL<sup>497</sup> mutation leads to the stronger MDR1h phenotype. B: Model for activation of drug-inducible activation of Mrr1 in sensitive strains, and different degrees of constitutive expression in MDR1 and MDR1h strains, leading to overexpression the AtrB drug efflux pump. The activation state of Mrr1 is indicated by colors (blue: inactive; orange, and red: active). From Hahn and Leroch (2015).

The second MDR type, called MDR2, has been detected so far only in French and German vineyards. MDR2-related mutations, leading to overexpression of the MFS-type efflux transporter MfsM2 and partial resistance to fenhexamid and cyprodinil, have probably originated in French vineyards and then spread towards Germany (Kretschmer et al., 2009; Mernke et al., 2011). In recent years, B. cinerea populations from strawberry fields showed dramatically increased fungicide resistance frequencies and high proportions of multiresistant strains that are resistant against several or even all of the currently registered fungicides (Leroch et al., 2013; Hahn et al., 2014; Fig. 2).

Fig. 2. Increase in resistance frequencies of <i>B. cinerea </i>strains between 2009-11 and 2013 in German strawberry fields. A: Frequencies of <i>B. cinerea </i>strains with resistance against QoIs, boscalid, fenhexamid, cyprodinil and fludioxonil (*partial resistance due to MDR1) (Leroch et al., 2013). B: Proportions of strains with no (sens) and increasing numbers of resistance against the registered fungicides (Switch: Mixture of cyprodinil and fludioxonil) are indicated by different colours. The red arrow marks the high proportion of ‘superresistant’ strains. (Rupp et al., in preparation)

Analysis of B. cinerea strawberry populations revealed the existence of different genetic groups that are distinct from the previously known B. cinerea genotypes. One of these groups, called B. cinerea S, was dominating in strawberry fields and showed a higher accumulation of fungicide resistance mutations than the common B. cinerea genotype N. In contrast, B. pse In addition, only B. cinerea S strains showed a stronger MDR1 variant called MDR1h, which confers higher levels of partial fludioxonil and cyprodinil resistance (Leroch et al., 2013; Fig. 3).

Fig. 3. Differential accumulation of fungicide resistances in strains of <i>B. cinerea </i>N and <i>B. cinerea </i>S in German strawberry fields. Proportions of strains with no (sensitive) and increasing numbers of resistances against the registered fungicides are shown. n: Number of strains. (Rupp et al., in preparation).

Literature

Konstantinou S, Veloukas T, Leroch M, Menexes G, Hahn M, Karaoglanidis G 2015. Population structure, fungicide resistance profile, and sdhB mutation frequency of Botrytis cinerea from strawberry and greenhouse-grown tomato in Greece. Plant Dis 99: 240-248.

Hahn M, Leroch M 2015. The role of multidrug efflux transporters in fungicide resistance of plant pathogenic fungi. In: Fungicide Resistance in Plant Pathogens: Principles and a Guide to Practical Management (Ishii H, Hollomon D., eds.), 2015, Springer Japan KK, Tokyo.

Hahn M 2014. The rising threat of fungicide resistance in plant pathogenic fungi: Botrytis as a case study. J. Chem. Biol., DOI 10.1007/s12154-014-0113-1.

Hahn M, Plesken C, Leroch M, Düker A, Rupp S, Weber R 2013. Multiple fungicide resistance and genetic diversity of Botrytis spp. in German strawberry fields. In: Dehne, H.W., Deising H.B., Fraaije B., Gisi U., Hermann D., Mehl A., Oerke E.C., Russell P.E., Stammler G., Kuck K.H. and Lyr H. (Eds) "Modern Fungicides and Antifungal Compounds", Vol. VII, pp. 1-xxx. Deutsche Phytomedizinische Gesellschaft, Braunschweig, ISBN: 978 3 941261 13 6.

Leroch M, Plesken C, Weber RWS, Kauff F, Scalliet G, Hahn M. 2013. Gray mold populations in German strawberry fields are resistant to multiple fungicides and dominated by a novel clade closely related to Botrytis cinerea. Appl Environ Microbiol 79: 159.

Mernke D, Dahm S, Walker AS, Lalève A, Fillinger S, Leroch M, Hahn M 2011. Two promoter rearrangements in a drug efflux transporter gene are responsible for the appearance and spread of multidrug resistance phenotype MDR2 in B. cinerea isolates in French and German vineyards. Phytopathology 101: 1176-1183.

Samuel S, Papayiannis LC, Leroch M, Veloukas T, Hahn M, Karaoglanidis GS 2011. Evaluation of the incidence of the G143A mutation and cytb intron presence in the cytochrome bc-1 gene conferring QoI resistance in Botrytis cinerea populations from several hosts. Pest Manag Sci 67: 1029-1036.

Veloukas T, Leroch M, Hahn M, Karaoglanidis GS 2011. Detection and molecular characterization of boscalid-resistant Botrytis cinerea isolates from strawberry. Plant Disease 95: 1302-1307.

Leroch M, Kretschmer M, Hahn M 2011. Fungicide resistance phenotypes of Botrytis cinerea isolates from commercial vineyards in South West Germany. J Phytopathol 159: 63–65.

Weber RWS, Hahn M 2011. A rapid and simple method for determining fungicide resistance in Botrytis. J Plant Dis Protect 108: 662-671.

Leroux P, Gredt M, Leroch M, Walker A-S 2010. Exploring mechanisms of resistance to respiratory inhibitors in field strains of Botrytis cinerea, the causal agent of gray mold. Appl Environ Microbiol 76: 6615–6630.

Kretschmer M, Leroch M, Mosbach A, Walker A-S, Fillinger S, Mernke D, Schoonbeek H-J, Pradier J-M, Leroux P, De Waard MA, Hahn M 2009. Fungicide-driven evolution and molecular basis of multidrug resistance in field populations of the grey mould fungus Botrytis cinerea. PLoS Pathog 5(12): e1000696.

Kretschmer M, Hahn M 2008. Fungicide resistance and genetic diversity of Botrytis cinerea isolates from a vineyard in Germany. J Plant Dis Protect 115: 214-219.

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