Trehalose-6-phosphate phosphatase inhibitor: N-(phenylthio) phthalimide, which can inhibit the DON biosynthesis of Fusarium graminearum

Xu, Chao; Chen, Hongzhou; Wu, Qinyan; Wu, Yuqi; Daly, Paul; Chen, Jian; Yang, Hongfu; Wei, Lihui; YiQing, Zhuang

doi:10.1016/j.pestbp.2021.104917

Cited by 5 publications

(3 citation statements)

References 54 publications

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“…Despite several initiatives, a clear inhibitor of Tps1 or Tps2 is not under clinical investigation, as far as we know. One publication shows an inhibitory effect of N-(phenylthio) phthalimide (NPP) on the Tps2 enzyme of the plant fungal pathogen Fusarium graminearum [54] while another study used T6P as a lead compound to develop Tps1 inhibitors [35]. Further research into developing Tps1 or Tps2 inhibitors is necessary to develop a novel class of antifungal drugs, that could work alone or in combination with existing drugs.…”

Section: Discussionmentioning

confidence: 99%

The stress-protectant molecule trehalose mediates fluconazole tolerance inCandida glabrata

Zhu,

Wijnants,

Feil

et al. 2024

Preprint

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The incidence of non-albicans Candidainfections has witnessed a substantial rise in recent decades.Candida glabrata (Nakaseomyces glabratus), an opportunistic human fungal pathogen, is accountable for both superficial mucosal and life-threatening bloodstream infections, particularly in immunocompromised individuals. Distinguished by its remarkable resilience to environmental stressors,C. glabrataexhibits intrinsic tolerance to azoles and a high propensity to swiftly develop azole resistance during treatment. The molecular mechanism for the high tolerance is not fully understood. In this work we investigated the possible role of trehalose in this tolerance. We generated mutants in theC. glabrata TPS1,TPS2, andNTH1genes, encoding trehalose 6-phosphate synthase (Tps1), trehalose 6-phosphate phosphatase (Tps2), and neutral trehalase (Nth1), respectively. As expected, thetps1Δstrain cannot grow on glucose. Thetps2Δ strain demonstrated diminished trehalose accumulation and very high levels of trehalose 6-phosphate (T6P), the biosynthetic intermediate, in comparison to the WT strain. Whereas these higher T6P levels did not affect growth, the lower trehalose levels clearly resulted in lower environmental stress tolerance and a lower susceptibility to fluconazole. More interestingly, thetps2Δstrain completely lost tolerance to fluconazole, characterized by the absence of slow growth at supra-MIC concentrations of this drug. All these phenotypes are reversed in thenth1Δ strain, which accumulates high levels of trehalose. Our findings underscore the role of trehalose in enabling tolerance towards fluconazole inC. glabrata. We further show that the change in tolerance is a result of the effect that trehalose has on the sterol pattern in the cell, showing that accumulation of ‘toxic’ sterols correlate with absence of tolerance.Author summaryC. glabratais a yeast of significant medical importance, known for causing nosocomial outbreaks of invasive candidiasis. Its propensity to develop resistance to antifungal medications, notably azoles such as fluconazole, raises considerable concern. An underlying reason for the rapid development of resistance is its intrinsic tolerance to this drug. The underlying molecular mechanism of tolerance to fluconazole is heavily studied but not understood. This study sheds light on the involvement of trehalose in modulating tolerance to fluconazole. We have elucidated that trehalose serves not only as a protective agent against various stresses but also as a mediator of fluconazole resistance and tolerance. To start elucidating how this may work, we provide data that trehalose (or the enzymes affecting the amount of trehalose in the cell) alters the ergosterol type and level in the cells, thereby affecting tolerance.

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Section: Discussionmentioning

confidence: 99%

The stress-protectant molecule trehalose mediates fluconazole tolerance inCandida glabrata

Zhu,

Wijnants,

Feil

et al. 2024

Preprint

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“…Because DON can inhibit DNA, RNA, and protein synthesis and impair the immune response of humans and animals [ 5 ], the excessive consumption of DON-contaminated wheat can cause symptoms such as vomiting, diarrhea, anemia, growth retardation, and even spermatogenesis disorders [ 6 , 7 ]. The FAO and WHO also list DON as one of the most dangerous natural food contaminants [ 8 ]. In China, the relative contamination of wheat by DON and its products in different regions is much higher than that of other mycotoxins, with detection rates ranging from 58.7% to 97.2%, exceeding rates (>1000 μg kg −1 ) ranging from 4.6% to 70%, and maximum detection concentrations reaching 3030 μg kg −1 to 56,100 μg kg −1 [ 9 , 10 , 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of Fungicides and Nontarget Pesticides on Accumulation of the Mycotoxin Deoxynivlenol in Wheat

Ju,

Jiang,

Gao

et al. 2023

Toxics

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Deoxynivalenol (DON) is an important virulence factor of the Fusarium head blight of wheat and threatens the health of humans. The effect of fungicides on DON production after stressing wheat to produce H2O2 and the effect of nontarget pesticides on DON accumulation are largely unknown. Five pesticides were selected to explore the effect of pesticide-induced oxidative stress on DON production in vitro and in vivo. Epoxiconazole and hexaconazole significantly induced an increase in H2O2 in vitro, and H2O2 further stimulated the production of DON and the expression of the Tri5 gene. Imidacloprid, isoproturon, and mesosulfuron-methyl had no direct effect in vitro. All pesticides activated the activities of superoxide dismutase, catalase, and peroxidase in wheat and caused the excessive accumulation of H2O2. However, excessive H2O2 did not stimulate the accumulation of DON. Imidacloprid indirectly stimulated the production of DON in vivo, which may be due to its impact on the secondary metabolism of wheat. In brief, pesticide-induced H2O2 in vitro is an important factor in stimulating DON production, but the stressed physiological H2O2 in wheat is not sufficient to stimulate DON production. The bioaccumulation results indicated that imidacloprid and epoxiconazole increase the risk of DON contamination, especially under field spraying conditions.

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“…F. graminearum occurs worldwide, especially in humid and rainy temperate regions. Fusarium head blight caused by F. graminearum not only reduces wheat yield ( Lu and Faris, 2019 ), its pathogen also produces mycotoxins such as deoxynivalenol (DON) and zearalenone (ZEN) ( Zhang et al., 2019 ; Xu et al., 2021 ; Zhou et al., 2021 ). If the wheat and its products contaminated by mycotoxins are eaten by humans and animals, they will cause vomiting, diarrhea, abortion, stillbirth, and other problems, which pose a great threat to the health of human beings and animals ( Puri and Zhong, 2010 ; Zheng et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%

FgMet3 and FgMet14 related to cysteine and methionine biosynthesis regulate vegetative growth, sexual reproduction, pathogenicity, and sensitivity to fungicides in Fusarium graminearum

et al. 2022

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Fusarium graminearum is a destructive filamentous fungus, which widely exists in wheat and other cereal crops. Cysteine and Methionine are unique sulfur-containing amino acids that play an essential role in protein synthesis and cell life, but their functions and regulation in F. graminearum remain largely unknown. Here we identified two proteins, FgMet3 and FgMet14 in F. graminearum, which are related to the synthesis of cysteine and methionine. We found FgMet3 and FgMet14 were localized to the cytoplasm and there was an interaction between them. FgMet3 or FgMet14 deletion mutants (ΔFgMet3 and ΔFgMet14) were deficient in vegetative growth, pigment formation, sexual development, penetrability and pathogenicity. With exogenous addition of cysteine and methionine, the vegetative growth and penetrability could be completely restored in ΔFgMet3 and ΔFgMet14, while sexual reproduction could be fully restored in ΔFgMet3 and partially restored in ΔFgMet14. ΔFgMet3 and ΔFgMet14 exhibited decreased sensitivity to Congo red stress and increased sensitivity to SDS, NaCl, KCl, Sorbitol, Menadione, and Zn ion stresses. Moreover, FgMet3 and FgMet14 nonspecifically regulate the sensitivity of F. graminearum to fungicides. In conclusion, FgMet3 and FgMet14 interacted to jointly regulate the development, pathogenicity, pigment formation, sensitivity to fungicides and stress factors in F. graminearum.

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Trehalose-6-phosphate phosphatase inhibitor: N-(phenylthio) phthalimide, which can inhibit the DON biosynthesis of Fusarium graminearum

Cited by 5 publications

References 54 publications

The stress-protectant molecule trehalose mediates fluconazole tolerance inCandida glabrata

The stress-protectant molecule trehalose mediates fluconazole tolerance inCandida glabrata

Effects of Fungicides and Nontarget Pesticides on Accumulation of the Mycotoxin Deoxynivlenol in Wheat

FgMet3 and FgMet14 related to cysteine and methionine biosynthesis regulate vegetative growth, sexual reproduction, pathogenicity, and sensitivity to fungicides in Fusarium graminearum

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