A new point mutation in β-tubulin confers resistance to carbendazim in Fusarium asiaticum

Yang, Ying; Li, Meixia; Duan, Yabing; Li, Tao; Shi, Yiyuan; Zhao, Dan; Zhou, Zehua; Xin, Wenjing; Wu, Jian; Pan, Xiayan; Li, Yanjun; Zhu, Yuanye; Zhou, Mingguo

doi:10.1016/j.pestbp.2017.12.006

Cited by 37 publications

(27 citation statements)

References 30 publications

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“…Benzimidazole suppressor screens in both Saccharomyces cerevisiae and Caenorhabditis elegans have independently identified resistance mutations occuring in β-tubulin genes, giving some insight into the binding site 29,30 . The case for a β-tubulin binding site is strengthened by numerous animal and agricultural studies also demonstrating resistance mutations arising repeatedly and independently across multiple parasitic nematode and fungal species infecting farm livestock and crops 22,27,[31][32][33][34][35][36][37][38][39][40][41][42][43] .…”

Section: Thiabendazole Disrupts Microtubule Plus Ends In Endothelial mentioning

confidence: 99%

“…Three commonly observed mutations in fungal and nematode β-tubulins (F200Y, E198A, and F167Y) confer resistance to TBZ ( Fig. 2A, B), suggesting that its binding site is in the vicinity of these residues 22,27,[31][32][33][34][35][36][37][38][39][40][41][42][43] (File S1). Based on the previously observed benzimidazole suppressor 6 mutations, we used 3D structural modeling to evaluate TBZ's potential binding sites in a fungal β-tubulin.…”

Section: Thiabendazole Selectively Targets Tubb8 Among Human β-Tubulinsmentioning

confidence: 99%

“…Given the plethora of fungal and nematode studies on benzimidazole pesticide resistance in agriculture 22,[33][34][35][36]38,[40][41][42][43][44][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71] (Fig. 4A), we reasoned that TBZ's molecular mechanism may extend to other commercially used benzimidazole compounds.…”

Section: Benzimidazole Resistance Patterns and Chemical Similarities mentioning

confidence: 99%

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Antifungal benzimidazoles disrupt vasculature by targeting one of nine β-tubulins

Garge

Lee

et al. 2020

Preprint

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Thiabendazole (TBZ) is an FDA-approved benzimidazole widely used for its antifungal and antihelminthic properties. We showed previously that TBZ is also a potent vascular disrupting agent and inhibits angiogenesis at the tissue level by dissociating vascular endothelial cells in newly formed blood vessels. Here, we uncover TBZ’s molecular target and mechanism of action. Using human cell culture, molecular modeling, and humanized yeast, we find that TBZ selectively targets only 1 of 9 human β-tubulin isotypes (TUBB8) to specifically disrupt endothelial cell microtubules. By leveraging epidemiological pesticide resistance data and mining chemical features of commercially used benzimidazoles, we discover that a broader class of benzimidazole compounds, in extensive use for 50 years, also potently disrupt immature blood vessels and inhibit angiogenesis. Thus, besides identifying the molecular mechanism of benzimidazole-mediated vascular disruption, this study presents evidence relevant to the widespread use of these compounds while offering potential new clinical applications.

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Section: Thiabendazole Disrupts Microtubule Plus Ends In Endothelial mentioning

confidence: 99%

Section: Thiabendazole Selectively Targets Tubb8 Among Human β-Tubulinsmentioning

confidence: 99%

Section: Benzimidazole Resistance Patterns and Chemical Similarities mentioning

confidence: 99%

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Antifungal benzimidazoles disrupt vasculature by targeting one of nine β-tubulins

Garge

Lee

et al. 2020

Preprint

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“…Most cases of MBC resistance in phytopathogenic fungi involve an alteration in an amino acid in ß‐tubulin, which is encoded by the ß‐tubulin gene. The amino acid alteration can lead to the loss of the fungicide's ability to bind to the target protein, resulting in benzimidazole resistance (Aguayo‐Ortiz et al., 2013; Cooley & Caten, 1993; Davidse & Flash, 1977; Jung, Wilder, & Oakley, 1992; Reijo, Cooper, Beagle, & Huffaker, 1994; Vela‐Corcía, Romero, Vicente, & Pérez‐García, 2018; Yang et al, 2018). Previous studies reported that a point mutation at codon 6, 50, 167, 198, 200, 240, or double‐point mutations at codon 79 and 102, in ß‐tubulin gene can be the cause and or related to MBC resistance in fungi (Kummanid et al, 2017; Ma & Michilide, 2005).…”

Section: Introductionmentioning

confidence: 99%

Detection and molecular characterization of carbendazim‐resistant Colletotrichum truncatum Isolates causing anthracnose of soybean in Thailand

Poti

Mahawan

Cheewangkoon

et al. 2020

Journal of Phytopathology

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A loss of fungicide efficacy, particularly for carbendazim, was noted in soybean fields in Thailand and was considered to be due to the development of Colletotrichum truncatum resistance. The carbendazim sensitivity of C. truncatum populations isolated from various soybean fields in Thailand was thus evaluated with in vitro sensitivity assays and molecular characterization of mutations in the sequences of the ß2‐tubulin (TUB2) gene that confer carbendazim resistance in the pathogen. Among 52 isolates, 46 isolates were classified as highly resistant (HR) to carbendazim (EC50 > 1,000 µg/ml). All HR isolates grew on PDA amended with carbendazim at 1,000 µg/ml. Six isolates were classified as carbendazim sensitive (S) (EC50 < 1 µg/ml). Mycelial growth on PDA amended with 1 µg/ml carbendazim was inhibited by over 50% compared with growth on PDA alone. When a partial TUB2 gene from the isolates was amplified and analysed using predicted amino acid sequences, an alteration from glutamic acid to alanine at codon 198 (E198A) was found in 45 HR isolates for which the EC50 was higher than 2000 µg/ml. This mutation resulted from a nucleotide substitution from adenine to cytosine (GAG → GCG). The other HR isolate, CtPhS_1, with EC50 of 1,127 µg/ml, had an alteration at codon 200 (F200Y) (TTC → TAC).

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“…Um grande problema enfrentado por pesticidas dessa classe é que a sua ação ocorre em apenas uma única proteína, a β-tubulina, tornando frequente o surgimento de espécies resistentes à ação desses compostos 18,19 . Por todos os motivos apresentados, a utilização de compostos dessa classe que sejam menos tóxicos, menos resistentes à degradação no meio ambiente e misturas desses com outros pesticidas vem sendo testadas.…”

Section: Figura 1 Utilização Mundial De Pesticidas Entre 1990 E 2016 unclassified

Estudo QSAR aplicado a pesticidas benzimidazólicos para a análise de risco ambiental

Peruquetti¹

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Estudos ambientais vêm ganhando força desde o século passado, com a crescente preocupação da manutenção de um meio ambiente equilibrado. Com a crescente demanda de conhecimento do comportamento de substâncias químicas, novas alternativas surgiram, dentre elas, as técnicas computacionais ou in silico. Uma importante ferramenta in silico são os estudos QSAR, que podem ser empregados na predição de diversas propriedades de substâncias químicas. O objetivo deste trabalho é estudar, com o auxílio de um modelo QSAR, a DL50 aguda oral para ratos de uma série de pesticidas benzimidazólicos pouco conhecidos, para posterior aplicação em estudos de análise de risco. Métodos de estrutura eletrônica, como os métodos DFT, foram empregados na obtenção de descritores para a criação do modelo de QSAR, bem como cálculo de espectros de infravermelho teóricos. Além das doses letais calculadas pelo QSAR, foram calculadas DL50 por meio de softwares livres disponíveis. Os cálculos de otimização geométrica e propriedades físico-químicas foram bem-sucedidos, assim como a criação dos espectros, gerando dados importantes para a criação dos modelos de QSAR. Os valores de DL50 obtidos, tanto pelos modelos construídos quanto pelos programas, apresentaram correlação com os valores experimentais disponíveis na literatura. Por meio desse estudo foi possível, ainda, realizar a classificação da maioria das moléculas de acordo com a cada classe toxicológica estabelecida pela EMBRAPA. Os modelos de QSAR foram validados interna e externamente, tiveram seus domínios de aplicabilidade definidos, foi averiguada a não ambiguidade de seus algoritmos e possibilitaram a determinação de um possível mecanismo de ação. Atingindo todos esses pontos, eles atingiram diretrizes da OECD. A aplicação de todas as técnicas empregadas fica evidenciada com clareza, já que os métodos utilizados apresentam alternativas rápidas e baratas, capazes de realizar estudos de grandes quantidades de pesticidas em pouco tempo. É possível concluir que todos os objetivos deste trabalho foram atingidos satisfatoriamente, já que os resultados obtidos foram de alta qualidade e aplicabilidade. Palavras-chave: QSAR, quimiometria, pesticidas benzimidazólicos, química computacional, análise de risco ambiental, toxicidade in silico.

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A new point mutation in β-tubulin confers resistance to carbendazim in Fusarium asiaticum

Cited by 37 publications

References 30 publications

Antifungal benzimidazoles disrupt vasculature by targeting one of nine β-tubulins

Antifungal benzimidazoles disrupt vasculature by targeting one of nine β-tubulins

Detection and molecular characterization of carbendazim‐resistant Colletotrichum truncatum Isolates causing anthracnose of soybean in Thailand

Estudo QSAR aplicado a pesticidas benzimidazólicos para a análise de risco ambiental

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