Strobilurins resistance

In the nineties a new compound class, the strobilurins, was introduced into the market. In Europe azoxystrobin and kresoxim-methyl were heavily used in cereals and the established product concepts and treatment systems had to be adjusted. Namely the importance of anti-resistance management (ARM) was recognized as a key factor in managing crop treatments and product portfolios. Therefore, contrary to first assumptions, product classes like the morpholines were not substituted directly by this new chemistry, but added as a complement to new product combinations to suppress resistance build vp. 

The fungicides are very versatile in the contol of fungi that have become resistant to the demethylase inhibitor (DMI) fungicides described later. They have surprisingly low mammalian toxicity, but as with many other respiratory poisons, they show some toxicity to fish and other aquatic organisms. They may also be toxic to earthworms. In fungi they inhibit spore germination. The structures show the natural products strobilurin B and azoxystrobin, which has been marketed since 1996. 

From these trials, it became clear that penthiopyrad shows no cross-resistance to DM I fungicides or strobilurin fungicides. 

With the introduction of Be 1 complex inhibitors (Chapter 13.2) in 1996, which act on the electron transport of fungi cells, the most important new compound class called strobilurins, derived from the natural compound Strobilurin A, was introduced in the reference period to the market. Chapter 13 describes the biochemistry of oxidative phosphorylation and of the related compounds and compound classes acting at different sites, reflecting the importance of these targets for the fungicide market nowadays. At the same time it became evident that resistance development, e.g., in the compound class of strobilurins must not lead necessarily to the abandonment of the marketing, research and development of such chemistry. 

C3 11 Complex III cytochrome bcl (ubiquinol oxidase) at Qo site Qol fungicides Strobilurins and related Azoxystrobin, Pyradostrobin Mostly broad spectmm high resistance risk... 

Fig. 13.2.6. Model of the hydrogen bridge between Glu 272 (yeast protein numbering) of the bq complex and the carbonyl group of a strobilurin pharmacophore. (Adapted from Refs. [8, 60, 61].) Glyl43 indicates the area of steric repulsion between strobilurins and the resistant Glyl43Ala mutants. The torsion of the pharmacophore relative to the side chain S is adapted from the active, torsionally restricted (+)-enantiomer in Ref [65].

Since zoxamide has a different mode of action from other products used in the Oomycete market, there is no likelihood of cross-resistance to existing products such as metalaxyl, dimethomorph, cymoxanil or strobilurins. Consequently, zoxamide provides a unique tool for resistance management in the Oomycete fungicide market. 

The cytochrome be, complex of Saccharomyces cerevisiae. A few amino acids (shown in blue) In Strobilurus tenacellus are responsible for Its natural resistance to strobilurins and oudemansins (binding pockets Qo and Qi ochre, b and b haem pink, FeS cluster yellow and brown). 

---