Abstract
Succinate dehydrogenase inhibitor (SDHI) fungicides are widely used for the control of a broad range of fungal diseases. This has been the most rapidly expanding fungicide group in terms of new molecules discovered and introduced for agricultural use over the past fifteen years. A particular pattern of differential sensitivity (resistance) to the stretched heterocycle amide SDHIs (SHA-SDHIs), a subclass of chemically-related SDHIs, was observed in naïve Zymoseptoria tritici populations not previously exposed to these chemicals. Subclass-specific resistance was confirmed at the enzyme level but did not correlate with the genotypes of the succinate dehydrogenase (SDH) encoding genes. Mapping and characterization of the molecular mechanisms responsible for standing SHA-SDHI resistance in natural field isolates identified a gene paralog of SDHC, termed ZtSDHC3, which encodes for an alternative C subunit of succinate dehydrogenase, named alt-SDHC. Using reverse genetics, we showed that alt-SDHC associates with the three other SDH subunits, leading to a fully functional enzyme and that a unique Qp-site residue within the alt-SDHC protein confers SHA-SDHI resistance. Enzymatic assays, computational modelling and docking simulations for the two SQR enzymes (altC-SQR, WT_SQR) enabled us to describe enzyme-inhibitor interactions at an atomistic level and to propose rational explanations for differential potency and resistance across SHA-SDHIs. European Z. tritici populations displayed a presence (20–30%) / absence polymorphism of ZtSDHC3, as well as differences in ZtSDHC3 expression levels and splicing efficiency. These polymorphisms have a strong impact on SHA-SDHI resistance phenotypes. Characterization of the ZtSDHC3 promoter in European Z. tritici populations suggests that transposon insertions are associated with the strongest resistance phenotypes. These results establish that a dispensable paralogous gene determines SHA-SDHIs fungicide resistance in natural populations of Z. tritici. This study paves the way to an increased awareness of the role of fungicidal target paralogs in resistance to fungicides and demonstrates the paramount importance of population genomics in fungicide discovery.
Highlights
Fungicide research is driven by the discovery of molecules with novel modes of action or acting on known targets but either displaying a novel spectrum of biological activity or escaping previously developed resistance mechanisms [1]
Zymoseptoria tritici is the causal agent of Septoria tritici leaf blotch (STB) of wheat, the most devastating disease for cereal production in Europe
The EC50 of these isolates was determined in liquid growth assays and the data obtained compared for each possible pair of Succinate dehydrogenase inhibitor (SDHI) fungicides (cross-resistance (XR) plots, Fig 1)
Summary
Fungicide research is driven by the discovery of molecules with novel modes of action or acting on known targets but either displaying a novel spectrum of biological activity or escaping previously developed resistance mechanisms [1]. The fungal SQR is highly variable across species, mainly because of a low sequence conservation of the internal mitochondrial membrane (IMM) SDHC and D subunits [4]. These target variations have a big impact on the biological spectrum of activity of carboxamide SDHIs [5]. In 2003, boscalid was released as the first foliar SDHI with a broadened spectrum of activity, enabling the control of diseases caused by ascomycetes [8]. The speed of resistance development and its practical impact on STB control has been contained, based on recommendations limiting the number of applications in spray programs and the use of mixtures with molecules carrying different modes of action
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