Azole fungicides - understanding resistance mechanisms in agricultural fungal pathogens

Price, Claire; Parker, Josie E.; Warrilow, Andrew G. S.; Kelly, Diane; Kelly, Steven L.

doi:10.1002/ps.4029

Cited by 248 publications

(172 citation statements)

References 52 publications

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“…Prothioconazole, which is a pro-fungicide and is metabolised to the active desthio form, generates lower resistance levels than other azoles in many pathogens, and this is linked to a somewhat different mode of action (Price et al 2015), When bound to the target sterol, 14α sterol demethylase (CYP51), the active form generates a novel spectrum which indicates it interacts differently with the target enzyme than do other azoles.…”

Section: Finding New Modes Of Actionmentioning

confidence: 99%

Fungicide resistance: facing the challenge - a review

Hollomon¹

2015

Plant Prot. Sci.

134

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Hollomon D.W. (2015): Fungicide resistance: facing the challenge. Plant Protect. Sci., Fungicide resistance continues to generate disease control problems in many crops. Experience amassed over the past fifty years has emphasised the importance of diversity in modes of action in anti-resistance strategies. Because of losses, not only from resistance, but increasingly from environmental and health concerns, the number of modes of action has become dangerously small. This paper considers three challenges facing crop protection in the search for durable disease control systems. Greater understanding of the biochemistry surrounding fungal development and pathogenicity provides opportunities for the discovery and development of novel modes of action, and some recent advances in this area are discussed. To ensure sufficient resources available to take a novel discovery forward to a commercial product, a second challenge facing manufacturers involves early assessment of resistance risk. A third challenge facing researchers, manufacturers and growers requires translation of resistance risk into effective and durable disease control strategies in actual crops. At the core of this challenge is using resistance risk evidence obtained in laboratory and glasshouse studies using individual isolates of target pathogens, to evaluate the fitness cost of resistance in pathogen populations in field crops. Increasingly, management of resistance is seen as the integration of fungicides with non-chemical disease control methods. But success of any Integrated Disease Management (IDM) strategy ultimately depends on the ability of growers to maintain production and profitability.

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Section: Finding New Modes Of Actionmentioning

confidence: 99%

Fungicide resistance: facing the challenge - a review

Hollomon¹

2015

Plant Prot. Sci.

134

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“…albicans Darlington strain [33], and TR46/Y121F/T289A in A . fumigatus CYP51A, which is thought to have arisen due to agricultural use of azoles [5, 6], confers resistance to VCZ. Other mutations have been associated with reduced susceptibility to azole agrochemicals.…”

Section: Discussionmentioning

confidence: 99%

“…While numerous classes of antimycotics are employed in agriculture, such as the benzimidazoles, phenylamides, dicarboximides, anilinopyrimidines, quinone outside inhibitors and carboxylic amides, the triazole antifungals alone account for ~20% of the global market share for systemic fungicides. In the United Kingdom prothioconazole (PTZ), tebuconazole (TBZ) and epoxiconazole are the three most commonly used fungicides [6]. In addition, the azoles are well suited for use in agriculture, since in some cases they have the advantage of enhancing crop growth independent of their effects on phytopathogens [7].…”

Section: Introductionmentioning

confidence: 99%

Structural and Functional Elucidation of Yeast Lanosterol 14α-Demethylase in Complex with Agrochemical Antifungals

et al. 2016

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Azole antifungals, known as demethylase inhibitors (DMIs), target sterol 14α-demethylase (CYP51) in the ergosterol biosynthetic pathway of fungal pathogens of both plants and humans. DMIs remain the treatment of choice in crop protection against a wide range of fungal phytopathogens that have the potential to reduce crop yields and threaten food security. We used a yeast membrane protein expression system to overexpress recombinant hexahistidine-tagged S. cerevisiae lanosterol 14α-demethylase and the Y140F or Y140H mutants of this enzyme as surrogates in order characterize interactions with DMIs. The whole-cell antifungal activity (MIC50 values) of both the R- and S-enantiomers of tebuconazole, prothioconazole (PTZ), prothioconazole-desthio, and oxo-prothioconazole (oxo-PTZ) as well as for fluquinconazole, prochloraz and a racemic mixture of difenoconazole were determined. In vitro binding studies with the affinity purified enzyme were used to show tight type II binding to the yeast enzyme for all compounds tested except PTZ and oxo-PTZ. High resolution X-ray crystal structures of ScErg11p6×His in complex with seven DMIs, including four enantiomers, reveal triazole-mediated coordination of all compounds and the specific orientation of compounds within the relatively hydrophobic binding site. Comparison with CYP51 structures from fungal pathogens including Candida albicans, Candida glabrata and Aspergillus fumigatus provides strong evidence for a highly conserved CYP51 structure including the drug binding site. The structures obtained using S. cerevisiae lanosterol 14α-demethylase in complex with these agrochemicals provide the basis for understanding the impact of mutations on azole susceptibility and a platform for the structure-directed design of the next-generation of DMIs.

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“…However, resistance to fungicides is well-documented throughout the world, and it threatens food security and human health [20,21]. …”

Section: Introductionmentioning

confidence: 99%

Antifungal and Antiaflatoxigenic Methylenedioxy-Containing Compounds and Piperine-Like Synthetic Compounds

Moon

Choi

Park

et al. 2016

Toxins

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Twelve methylenedioxy-containing compounds including piperine and 10 piperine-like synthetic compounds were assessed to determine their antifungal and antiaflatoxigenic activities against Aspergillus flavus ATCC 22546 in terms of their structure–activity relationships. Piperonal and 1,3-benzodioxole had inhibitory effects against A. flavus mycelial growth and aflatoxin B1 production up to a concentration of 1000 μg/mL. Ten piperine-like synthetic compounds were synthesized that differed in terms of the carbon length in the hydrocarbon backbone and the presence of the methylenedioxy moiety. In particular, 1-(2-methylpiperidin-1-yl)-3-phenylprop-2-en-1-one had potent antifungal and antiaflatoxigenic effects against A. flavus up to a concentration of 1 μg/mL. This synthetic compound was remarkable because the positive control thiabendazole had no inhibitory effect at this concentration. Reverse transcription-PCR analysis showed that five genes involved in aflatoxin biosynthesis pathways were down-regulated in A. flavus, i.e., aflD, aflK, aflQ, aflR, and aflS; therefore, the synthetic compound inhibited aflatoxin production by down-regulating these genes.

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Azole fungicides - understanding resistance mechanisms in agricultural fungal pathogens

Cited by 248 publications

References 52 publications

Fungicide resistance: facing the challenge - a review

Fungicide resistance: facing the challenge - a review

Structural and Functional Elucidation of Yeast Lanosterol 14α-Demethylase in Complex with Agrochemical Antifungals

Antifungal and Antiaflatoxigenic Methylenedioxy-Containing Compounds and Piperine-Like Synthetic Compounds

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