Discovery of metyltetraprole: Identification of tetrazolinone pharmacophore to overcome QoI resistance

Matsuzaki, Yuichi; Yoshimoto, Yuya; Arimori, Sadayuki; Kiguchi, So; Harada, Toshiyuki; Iwahashi, Fukumatsu

doi:10.1016/j.bmc.2019.115211

Cited by 29 publications

(33 citation statements)

References 8 publications

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“…But still, many fungi can express an alternative QH2oxidase that bypasses complex III and IV and confer resistance to this type of blocking agent (Vanlerberghe and McIntosh, 1997). Metyltetraprole, the first member of a new generation of QoIs, has a stable efficiency both in greenhouses and in the fields, even in the presence of G143A resistant mutants (Matsuzaki et al, 2020).…”

Section: The Mitogenome Its Role In Fungal Virulence and A Target Ofmentioning

confidence: 99%

Fungal Mitogenomes: Relevant Features to Planning Plant Disease Management

et al. 2020

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Mitochondrial genomes (mt-genomes) are characterized by a distinct codon usage and their autonomous replication. Mt-genomes encode highly conserved genes (mt-genes), like proteins involved in electron transport and oxidative phosphorylation but they also carry highly variable regions that are in part responsible for their high plasticity. The degree of conservation of their genes is such that they allow the establishment of phylogenetic relationships even across distantly related species. Here, we describe the mechanisms that generate changes along mt-genomes, which play key roles at enlarging the ability of fungi to adapt to changing environments. Within mt-genomes of fungal pathogens, there are dispensable as well as indispensable genes for survival, virulence and/or pathogenicity. We also describe the different complexes or mechanisms targeted by fungicides, thus addressing a relevant issue regarding disease management. Despite the controversial origin and evolution of fungal mt-genomes, the intrinsic mechanisms and molecular biology involved in their evolution will help to understand, at the molecular level, the strategies for fungal disease management.

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Section: The Mitogenome Its Role In Fungal Virulence and A Target Ofmentioning

confidence: 99%

Fungal Mitogenomes: Relevant Features to Planning Plant Disease Management

et al. 2020

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“…Recently, Matsuzaki and coworkers [ 36 ] obtained new Qo inhibitors characterized by a tetrazolinone pharmacophore and a methyl group at position 3 on the central phenyl ring. These compounds were designed to overcome the resistance developed by different pathogenic species and associated with the G143A mutation at the target site.…”

Section: Strobilurinsmentioning

confidence: 99%

Natural Compound-Derived Cytochrome bc1 Complex Inhibitors as Antifungal Agents

2020

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The high incidence of fungal pathogens has become a global issue for crop protection. A promising strategy to control fungal plant infections is based on the use of nature-inspired compounds. The cytochrome bc1 complex is an essential component of the cellular respiratory chain and is one of the most important fungicidal targets. Natural products have played a crucial role in the discovery of cytochrome bc1 inhibitors, as proven by the development of strobilurins, one of the most important classes of crop-protection agents, over the past two decades. In this review, we summarize advances in the exploration of natural product scaffolds for the design and development of new bc1 complex inhibitors. Particular emphasis is given to molecular modeling-based approaches and structure–activity relationship (SAR) studies performed to improve the stability and increase the potency of natural precursors. The collected results highlight the versatility of natural compounds and provide an insight into the potential development of nature-inspired derivatives as antifungal agents.

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“…1,2 Metyltetraprole, 1-(2-{[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy methyl}-3-methylphenyl)-1,4-dihydro-4-methyl-5H-tetrazol-5-one, is a novel fungicide with the unique tetrazolinone pharmacophore found by Sumitomo Chemical Co. Ltd. [5][6][7][8] Its molecule has a side chain very similar to that of pyraclostrobin, a representative of the existing QoIs, and it also binds to the Qo site of the cytochrome bc1 complex. 5,9 A competitive binding assay using radiolabeled metyltetraprole and pyraclostrobin showed that both fungicides bound to the same target pocket in the cytochrome bc1 complex. 5 Nevertheless, it was previously demonstrated to be highly active even against the Z. tritici and P. teres strains harboring the mutations G143A and F129L, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…5,9 A competitive binding assay using radiolabeled metyltetraprole and pyraclostrobin showed that both fungicides bound to the same target pocket in the cytochrome bc1 complex. 5 Nevertheless, it was previously demonstrated to be highly active even against the Z. tritici and P. teres strains harboring the mutations G143A and F129L, respectively. 7 Therefore, metyltetraprole is considered to be the first molecule of a new innovative generation of QoIs.…”

Section: Introductionmentioning

confidence: 99%

“…Its molecule has a side chain very similar to that of pyraclostrobin, a representative of the existing QoIs, and it also binds to the Qo site of the cytochrome bc 1 complex . A competitive binding assay using radiolabeled metyltetraprole and pyraclostrobin showed that both fungicides bound to the same target pocket in the cytochrome bc 1 complex . Nevertheless, it was previously demonstrated to be highly active even against the Z. tritici and P. teres strains harboring the mutations G143A and F129L, respectively .…”

Section: Introductionmentioning

confidence: 99%

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Antifungal activity of metyltetraprole against the existing QoI‐resistant isolates of various plant pathogenic fungi

Matsuzaki

Kiguchi

Suemoto

et al. 2019

Pest Management Science

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BACKGROUND Metyltetraprole is a novel quinol oxidation site of Complex III inhibitor (QoI) fungicide that inhibits mitochondrial electron transport at the Qo site of the cytochrome bc1 complex. Previous reports have demonstrated that it is also active against the QoI‐resistant (QoI‐R) isolates of Zymoseptoria tritici and Pyrenophora teres with the mutations G143A and F129L in their cytochrome b gene, respectively. Further studies on cross‐resistance between metyltetraprole and existing QoIs were performed using an increased number of isolates of Z. tritici, P. teres, Ramularia collo‐cygni, Pyrenophora tritici‐repentis, and several other plant pathogenic fungi. RESULTS Differences in the EC50 values between the wild‐type and QoI‐R isolates with the mutations G143A or F129L were always smaller for metyltetraprole compared to those for the existing QoIs, and they were never greater than five in terms of resistance factor. The 2‐year field experiments showed that the metyltetraprole treatment did not increase the percentage of QoI‐R isolates likely to harbor the G143A mutation in a Z. tritici population. CONCLUSION The unique behavior of metyltetraprole against the existing QoI‐R isolates was confirmed for all tested pathogen species. Our results provide important information to establish a fungicide resistance management strategy using metyltetraprole in combination or alternation with other fungicides. © 2019 Society of Chemical Industry

show abstract

Discovery of metyltetraprole: Identification of tetrazolinone pharmacophore to overcome QoI resistance

Cited by 29 publications

References 8 publications

Fungal Mitogenomes: Relevant Features to Planning Plant Disease Management

Fungal Mitogenomes: Relevant Features to Planning Plant Disease Management

Natural Compound-Derived Cytochrome bc1 Complex Inhibitors as Antifungal Agents

Antifungal activity of metyltetraprole against the existing QoI‐resistant isolates of various plant pathogenic fungi

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