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植物病原真菌对甾醇脱甲基抑制剂类杀菌剂抗性分子机制研究进展

刘凤华 马迪成 张晓敏 李金 刘峰 慕卫

刘凤华, 马迪成, 张晓敏, 李金, 刘峰, 慕卫. 植物病原真菌对甾醇脱甲基抑制剂类杀菌剂抗性分子机制研究进展[J]. 农药学学报, 2022, 24(3): 452-464. doi: 10.16801/j.issn.1008-7303.2022.0008
引用本文: 刘凤华, 马迪成, 张晓敏, 李金, 刘峰, 慕卫. 植物病原真菌对甾醇脱甲基抑制剂类杀菌剂抗性分子机制研究进展[J]. 农药学学报, 2022, 24(3): 452-464. doi: 10.16801/j.issn.1008-7303.2022.0008
LIU Fenghua, MA Dicheng, ZHANG Xiaomin, LI Jin, LIU Feng, MU Wei. Research progress on molecular resistance mechanism of plant pathogenic fungi to sterol demethylase inhibitors[J]. Chinese Journal of Pesticide Science, 2022, 24(3): 452-464. doi: 10.16801/j.issn.1008-7303.2022.0008
Citation: LIU Fenghua, MA Dicheng, ZHANG Xiaomin, LI Jin, LIU Feng, MU Wei. Research progress on molecular resistance mechanism of plant pathogenic fungi to sterol demethylase inhibitors[J]. Chinese Journal of Pesticide Science, 2022, 24(3): 452-464. doi: 10.16801/j.issn.1008-7303.2022.0008

植物病原真菌对甾醇脱甲基抑制剂类杀菌剂抗性分子机制研究进展

doi: 10.16801/j.issn.1008-7303.2022.0008
基金项目: 山东省蔬菜产业技术体系 (SDAIT-05);国家自然科学基金 (31772203).
详细信息
    作者简介:

    刘凤华,18864820696 @163.com

    通讯作者:

    刘峰,fliu@sdau.edu.cn

    慕卫,muwei@sdau.edu.cn

  • 中图分类号: S482.2

Research progress on molecular resistance mechanism of plant pathogenic fungi to sterol demethylase inhibitors

Funds: the Modern Agricultural Industry Technology System for Vegetables in Shandong Province (SDAIT-05), the National Natural Science Foundation of China (31772203)
  • 摘要: 甾醇脱甲基抑制剂 (DMI) 可通过抑制病原真菌的14α-去甲基化酶(CYP51)而干扰或阻断细胞膜麦角甾醇的生物合成,造成有毒甾醇积累,从而影响细胞膜的结构及功能,进而发挥抗菌作用。随着DMI类杀菌剂的广泛应用,病原菌对其的抗性问题日益严重。本文从抗药性分子机制出发,总结出病原菌对DMI类杀菌剂产生抗性的主要原因为:CYP51氨基酸突变引起其与杀菌剂间的亲和力下降;启动子区域基因片段的插入引起CYP51基因过表达;转录因子激活突变或启动子区域基因片段插入导致外排蛋白基因过表达。本文基于杀菌剂的作用方式及病原菌抗性机制研究展开综述,可为杀菌化合物的结构修饰与优化、新靶点改进和研发以及病原真菌的抗药性治理提供参考。
  • 图  1  CYP51催化的羊毛甾醇14α-脱甲基化反应[21]

    Figure  1.  The 14α-demethylation mechanism of lanosterol catalyzed by CYP51[21]

    图  2  不同类型小麦叶枯病菌CYP51与三唑类药剂分子对接模型[48]

    注: (A) 野生型CYP51与三唑醇分子对接模型, 三唑醇的氯基和Y137形成的弱氢键,蛋白质的I螺旋沿着三唑醇左边向下延伸,而I381后面的K螺旋向下延伸到血红素基团后方,L50和A379不直接与结合腔接触,但会形成紧挨着腔体的二级结构,S188和N513位于蛋白质的外侧,远离结合区域。 (B) ΔY459/Y461H突变体与戊唑醇分子对接模型,Y137在结合范围外,而K133和K148被引入结合区域。 (C) Y137F突变体与三唑醇分子对接模型,F137和I381存在空间冲突,影响与三唑醇的结合。

    Figure  2.  Azole docking with different CYP51 proteins in Mycosphaerella graminicola[48]

    Note: (A) The docking model of triadimenol and wild type CYP51. The chloride group (green) of triadimenol is predicted to form a weak hydrogen bond with Y137. The I helix of CYP51 protein stretches down along the left of the bound azole and the K helix behind I381 extends down to rear of the haem group. L50 and A379 do not directly border the binding cavity but form part of secondary structures in close proximity to the cavity. S188 and N513 are located outside of the protein, far from the binding regions. (B) The docking model of tebuconazole and ΔY459/Y461H mutated CYP51. Y137 is outside of the protein binding cavity, while K133 and K148 are introduced to the pocket close to the azole. (C) The docking model of triadimenol and Y137F mutated CYP51. F137 presents the spatial conflicts with I381, suggesting its binding with triadimenol would be significantly impaired.

    图  3  指状青霉PdCYP151启动子区域示意图[57]

    注: (A) 敏感菌株启动子区域均含有1个126 bp的转录增强子; (B) 大部分抗性菌株启动子区域含有1个126 bp的转录增强子和1个199 bp的插入序列; (C) 部分抗性菌株启动子区域含有5个126 bp的转录增强子;每个单箭头代表126 bp转录增强子,断箭头对应126 bp转录增强子和1个199 bp的插入序列。

    Figure  3.  A schematic diagram of the promoter region of the PdCYP51 gene in Penicillium digitatum[57]

    Note: (A) The promoter regions of sensitive isolates show a 126 bp transcription enhancement unit. (B) The promoter regions of most resistant isolates have a 126 bp transcription enhancement unit and a 199 bp insertion. (C) The promoter regions of some resistant isolates contain five 126 bp transcription enhancement units. Every single arrow represents a copy of the 126 bp transcriptional enhancer, while the broken arrow corresponds to the 126 bp transcriptional enhancer and a unique 199 bp insertion.

    表  1  CYP51氨基酸改变导致植物病原菌对DMI类杀菌剂产生抗性

    Table  1.   Amino acid alterations within CYP51 in plant pathogens are responsible for DMI fungicides resistance

    病原菌
    Pathogen
    突变类型
    Mutation type
    杀菌剂
    Fungicide
    参考文献
    Reference
    小麦白粉病菌 Blumeria graminis f. sp. hordei Y136F, K147Q 三唑醇 triadimeno
    丙环唑 propiconazole
    [29]
    小麦白粉病菌 Blumeria graminis f. sp. tritici Y136F, S79T, K175N 三唑醇 triadimeno
    丙环唑 propiconazole
    [29]
    胶孢炭疽菌
    Colletotrichum gloeosporioides
    CYP51A: L58V, S175P, A340S, T379A , N476TCYP51B:
    D121N, T132A, F391Y, T262A
    戊唑醇 tebuconazole丙环唑 propiconazole
    苯醚甲环唑 difenoconazole
    [30]
    葡萄白粉病菌
    Erysiphe necator
    Y136F 三唑醇 triadimeno
    氯苯嘧啶醇 fenarimol
    [31]
    水稻恶苗病菌
    Fusarium fujikuroi
    CYP51B: S312T 咪鲜胺 prochloraz [32]
    拟轮枝镰刀菌
    Fusarium verticillioides
    CYP51B: Y123H 咪鲜胺 prochloraz [33]
    桃褐腐病菌
    Monilinia fructicola
    S461G 丙环唑 propiconazole 戊唑醇 tebuconazole
    腈菌唑 myclobutanil
    [34]
    香蕉黑条叶斑病菌
    Mycosphaerella fijiensis
    Y136F, A313G, Y461D, A381G, G462A,Y463D/H/N 丙环唑 propiconazole
    环唑醇 cyproconazole
    [35]
    小麦叶枯病菌
    Mycosphaerella graminicola
    L50S, S188N, I381V, Y137F, S524T, ΔY459/G460, N513K, Y459D/N/P/S, G460D, Y461H/S/D, V136A, A379G, G312A, N513K,D134G, D107V,N284H A311G, S208T, A410T, G412A, N178S 三唑类 triazoles [17, 36-38]
    Oculimacula acuformis A29P, V37A, Q167H, Y486H, S505Q 咪鲜胺 prochloraz [39]
    Oculimacula yallundae S35T, Q43H, D78Y, E106K, N244S, S505Q 三唑类 triazoles [39]
    指状青霉
    Penicillium digitatum
    CYP51B: Q309H, Y136H, G459, F506I 咪鲜胺 prochloraz
    抑霉唑 imazalil
    [40]
    大麦网斑病菌
    Pyrenophora teres
    F489L 戊唑醇 tebuconazole [11]
    大豆疫霉
    Phakopsora pachyrhizi
    F120L + Y131H, Y131F + I475T, F120L + Y131F + I475T 戊唑醇 tebuconazole [41]
    小麦叶锈病菌
    Puccinia triticina
    Y134F 氟环唑 epoxiconazole [11]
    Parastagonospora nodorum Y144F/H 丙环唑 propiconazole [42]
    油菜核盘菌
    Sclerotinia sclerotiorum
    K244E 戊唑醇 tebuconazole [43]
    稻曲病菌
    Villosiclava virens
    Y137H 戊唑醇 tebuconazole [44]
    下载: 导出CSV

    表  2  CYP51基因过表达导致植物病原菌对DMI类杀菌剂产生抗性

    Table  2.   Overexpression of CYP51 in plant pathogens is responsible for to DMI fungicides resistance

    病原菌
    Pathogen
    插入位置
    Location
    插入序列长度
    Insertion length
    杀菌剂
    Fungicide
    参考文献
    Reference
    樱桃叶斑病
    Blumeriella jaapii
    −181 bp 5858 bp 腈苯唑 fenbuconazole [54]
    −102 bp 2120 bp, 2274 bp, 2461 bp 腈苯唑 fenbuconazole [54]
    桃褐腐病菌
    Monilinia fructicola
    −113 bp 65 bp 丙环唑 propiconazole [51]
    小麦叶枯病菌
    Mycosphaerella graminicola
    −83 bp 120 bp 氟环唑 epoxiconazole [53]
    油菜黑胫病菌
    Leptosphaeria maculans
    −102 bp 275 bp 戊唑醇 tebuconazole氟喹唑 fluquinconazole
    丙硫菌唑 prothioconazole粉唑醇 flutriafol
    [55]
    −347 bp 5263 bp
    −361 bp 5267 bp
    −379 bp 5248 bp
    指状青霉
    Penicillium digitatum
    CYP51A: −43 bp, −168 bp,
    −294 bp, −420 bp, −546 bp, −672 bp
    126 bp串联重复
    Tandem repeats of 126 bp
    氟菌唑 triflumizole氯氟醚菌唑 mefentrifluconazole
    双苯三唑醇 bitertanol
    [56]
    CYP51A: −43 bp 450 bp 氟菌唑 triflumizole氯氟醚菌唑 mefentrifluconazole
    双苯三唑醇 bitertanol
    [57]
    CYP51B: −174 bp 199 bp 氟菌唑 triflumizole氯氟醚菌唑 mefentrifluconazole
    双苯三唑醇 bitertanol
    [57]
    CYP51B: −174 bp 195 bp 氟菌唑 triflumizole氯氟醚菌唑 mefentrifluconazole
    双苯三唑醇 bitertanol
    [58]
    香蕉黑条叶斑病菌
    Mycosphaerella fijiensis
    −94 bp 103 bp 苯醚甲环唑 difenoconazole氟环唑 epoxiconazole
    丙环唑 propiconazole
    [52]
    −103 bp 100 bp 丙环唑 propiconazole
    环唑醇 cyproconazole
    [59]
    油菜光叶斑病
    Pyrenopeziza brassicae
    −316 bp 46 bp 戊唑醇 tebuconazol叶菌唑 metconazole氟硅唑 flusilazole丙硫菌唑 prothioconazole咪鲜胺 prochloraz [60]
    −346 bp 151 bp
    −180 bp 233 bp
    大麦网斑病菌
    Pyrenophora teres
    −46 bp, −66 bp, −74 bp, −75 bp, −90 bp 134 bp 戊唑醇 tebuconazol [15]
    苹果黑星病菌
    Venturia inaequalis
    −64 bp 533 bp 腈菌唑 myclobutanil [61]
    下载: 导出CSV
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  • 收稿日期:  2021-11-03
  • 录用日期:  2022-01-13
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