The cytochrome <i>bc</i><sub>1</sub> complex as an antipathogenic target

Fisher, Nicholas; Meunier, Brigitte; Biagini, Giancarlo A.

doi:10.1002/1873-3468.13868

Cited by 51 publications

(39 citation statements)

References 144 publications

(230 reference statements)

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“…These yeast mutants exhibited similar level of reduced sensitivity to florylpicoxamid, confirming the same Qi binding site and existence of cross‐resistance for the two picolinamide fungicides 33 . Amino acid exchanges for N31, G37, and L198 have been reported to confer resistance to other Qi inhibitors in different organisms 26,31,39 . Residue G37 appears to be a particular hot spot of resistance mutations.…”

Section: Resultsmentioning

confidence: 58%

“…Another non‐target site related resistance mechanism for QiI and QoI fungicides involves AOX, which bypasses complex III with 60% lower energy efficiency 19,26 . AOX‐linked resistance was initially observed on laboratory generated azoxystrobin resistant Z. tritici isolates 43 .…”

Section: Resultsmentioning

confidence: 99%

“…Mutations in one or more of the SdhB , SdhC or SdhD subunits of SDH enzyme have generated multiple genotypes of resistant fungal pathogens, with resistance factors from low to extremely high 7,11,13 . In the case of strobilurin fungicides, four amino acid changes G143A, G137R, G137S, and F129L were identified in field populations, with the G143A mutation responsible for the dramatic loss of efficacy in many commercial applications 6,26 …”

Section: Introductionmentioning

confidence: 99%

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Florylpicoxamid, a new picolinamide fungicide with broad spectrum activity

Yao

Meyer

Gallup

et al. 2021

Pest Management Science

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BACKGROUND Following the introduction of fenpicoxamid, a natural product‐based fungicide targeting the Qi site of mitochondrial cytochrome bc1 complex, a second generation fully synthetic picolinamide, florylpicoxamid, was discovered and its biological activity and attributes were characterized. RESULTS In vitro fungal growth inhibition assays and in planta glasshouse biological activity evaluations showed florylpicoxamid was active against 21 different plant pathogenic fungi within the phyla Ascomycota and Basidiomycota. Among the pathogens evaluated, florylpicoxamid was most potent against Zymoseptoria tritici, the causal organism of wheat leaf blotch, providing 80% growth inhibition in vitro at 0.0046 mg L−1 and 80% disease control in planta at 0.03 mg L−1 when applied as a preventative treatment. Florylpicoxamid was more efficacious than epoxiconazole, fluxapyroxad, and benzovindiflupyr versus a Z. tritici wild‐type isolate when applied as curative and preventative treatments, with superior 10‐day curative reachback activity. Analytical studies and in planta tests demonstrated that florylpicoxamid partitioned into plants quickly and showed good systemicity and translaminar activity on both monocot and dicot plants. No cross‐resistance was observed between florylpicoxamid and strobilurin or azole fungicides. Florylpicoxamid exerts its preventative effect by preventing spore germination on the leaf surface and curative activity by arresting mycelial growth and pycnidia development in leaf tissue. CONCLUSIONS With strong broad spectrum fungicidal activity, florylpicoxamid delivers an innovative solution for growers to sustain high productivity and quality of many crops, and also provides a new option for developing effective strategies for fungicide resistance management. © 2021 Society of Chemical Industry.

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Section: Resultsmentioning

confidence: 58%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Florylpicoxamid, a new picolinamide fungicide with broad spectrum activity

Yao

Meyer

Gallup

et al. 2021

Pest Management Science

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“…The major drawbacks of these fungicides are their toxicity to aquatic organisms and the increased number of fungal pathogens that are showing occurrence of resistance, mainly due to mutations on mitochondrial genes encoding for the Qo site [ 4 ].…”

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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“…Three subunits, cytochrome b , cytochrome c 1 and the Rieske iron-sulphur protein, form the catalytic core of the enzyme. Cytochrome b is encoded by the mitochondrial genome in all eukaryotes, and the other subunits are encoded by nuclear genes (reviewed in Berry et al ., 2000; Crofts, 2004; Fisher et al ., 2020). The complex possesses two distinct ubiquinone-binding sites situated on opposite sides of the IMM; the ubiquinol oxidation site (Q o site) located towards the IMM outer side, and the ubiquinone reduction site (Q i site) located towards the inner, or matrix, side.…”

Section: Introductionmentioning

confidence: 99%

Directed evolution predicts cytochrome b G37V target site modification as probable adaptive mechanism towards the QiI fungicide fenpicoxamid in Zymoseptoria tritici

Fouché

Michel

Lalève

et al. 2021

Preprint

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Acquired resistance is a threat for antifungal efficacy in medicine and agriculture. The diversity of possible resistance mechanisms, as well as the highly adaptive traits of pathogens make it difficult to predict evolutionary outcomes of treatments. We used directed evolution as an approach to assess the risk of resistance to the new fungicide fenpicoxamid in the wheat pathogenic fungus Zymoseptoria tritici. Fenpicoxamid inhibits complexIII of the respiratory chain at the ubiquinone reduction site (Qi site) of the mitochondrially encoded cytochrome b, a different site than the widely-used strobilurins which the respiratory complex by binding to the ubiquinol oxidation site (Qo site). We identified the G37V change, within the cytochrome b Qi site, as the most likely resistance mechanism to be selected in Z. tritici. This change triggered high fenpicoxamid resistance and halved the enzymatic activity of cytochrome b, despite no significant penalty for in vitro growth. In addition, we identified a negative cross-resistance between isolates harboring G37V or G143A, a Qo site change previously selected by strobilurins. Moreover, double mutants were less resistant to both QiIs and QoIs compared to single mutants. This work is a proof of concept that experimental evolution can be used to predict adaptation to fungicides, and provides new perspectives for the management of QiIs.

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The cytochrome bc₁ complex as an antipathogenic target

Cited by 51 publications

References 144 publications

Florylpicoxamid, a new picolinamide fungicide with broad spectrum activity

Florylpicoxamid, a new picolinamide fungicide with broad spectrum activity

Natural Compound-Derived Cytochrome bc1 Complex Inhibitors as Antifungal Agents

Directed evolution predicts cytochrome b G37V target site modification as probable adaptive mechanism towards the QiI fungicide fenpicoxamid in Zymoseptoria tritici

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The cytochrome bc1 complex as an antipathogenic target

Cited by 51 publications

References 144 publications

Florylpicoxamid, a new picolinamide fungicide with broad spectrum activity

Florylpicoxamid, a new picolinamide fungicide with broad spectrum activity

Natural Compound-Derived Cytochrome bc1 Complex Inhibitors as Antifungal Agents

Directed evolution predicts cytochrome b G37V target site modification as probable adaptive mechanism towards the QiI fungicide fenpicoxamid in Zymoseptoria tritici

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The cytochrome bc₁ complex as an antipathogenic target