Multiple mechanisms account for resistance to sterol 14α‐demethylation inhibitors in field isolates of <i>Mycosphaerella graminicola</i>

Leroux, Pierre; Walker, Anne Sophie

doi:10.1002/ps.2028

Cited by 188 publications

(292 citation statements)

References 53 publications

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“…Previous reports have confirmed the synergistic inhibitory activity of efflux blockers and DMI fungicides on the mycelial growth of fungal plant pathogens with ABC transportermediated fungicide resistance (13,20). Thus, our findings provide grounds to investigate the potential for ABC transporter efflux blockers in the treatment of dollar spot epidemics that cannot be adequately controlled by DMI fungicides alone.…”

Section: Discussionsupporting

confidence: 84%

“…2). The cooccurrence of CYP51 and ABC-G overexpressions in fungi with reduced DMI sensitivity is widespread and known for field isolates of fungal plant pathogens and clinical isolates of a human fungal pathogen (5,20). In Candida albicans, chromosomal aneuploidy and a subsequent loss of heterozygosity (LOH) give not only higher CYP51 gene expression levels but also simultaneous increases in expression levels of a transcriptional regulator, TAC1, of an ABC-G efflux gene (5,38).…”

Section: Discussionmentioning

confidence: 99%

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Overexpression of ShCYP51B and ShatrD in Sclerotinia homoeocarpa Isolates Exhibiting Practical Field Resistance to a Demethylation Inhibitor Fungicide

Hulvey

Popko

Sang

et al. 2012

Appl Environ Microbiol

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ABSTRACTWe investigated genetic factors that govern the reduced propiconazole sensitivity ofSclerotinia homoeocarpafield isolates collected during a 2-year field efficacy study on dollar spot disease of turf in five New England sites. These isolates displayed a >50-fold range ofin vitrosensitivity to a sterol demethylation inhibitor (DMI) fungicide, propiconazole, making them ideal for investigations of genetic mechanisms of reduced DMI sensitivity. TheCYP51gene homolog inS. homoeocarpa(ShCYP51B), encoding the enzyme target of DMIs, is likely a minor genetic factor for reduced propiconazole sensitivity, since there were no differences in constitutive relative expression (RE) values and only 2-fold-higher induced RE values for insensitive than for sensitive isolate groups. Next, we mined RNA-Seq transcriptome data for additional genetic factors and found evidence for the overexpression of a homolog ofBotrytis cinerea atrD(BcatrD),ShatrD, a known efflux transporter of DMI fungicides. TheShatrDgene showed much higher constitutive and induced RE values for insensitive isolates. Several polymorphisms were found upstream ofShatrDbut were not definitively linked to overexpression. The screening of constitutive RE values ofShCYP51BandShatrDin isolates from two golf courses that exhibited practical field resistance to propiconazole uncovered evidence for significant population-specific overexpression of both genes. However, linear regression demonstrated that the RE ofShatrDdisplays a more significant relationship with propiconazole sensitivity than that ofShCYP51B. In summary, our results suggest that efflux is a major determinant of the reduced DMI sensitivity ofS. homoeocarpagenotypes in New England, which may have implications for the emergence of practical field resistance in this important turfgrass pathogen.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Overexpression of ShCYP51B and ShatrD in Sclerotinia homoeocarpa Isolates Exhibiting Practical Field Resistance to a Demethylation Inhibitor Fungicide

Hulvey

Popko

Sang

et al. 2012

Appl Environ Microbiol

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“…The most recently introduced azole is the triazolinethione derivative prothioconazole. However, the control of this disease has been threatened by the identification of mutations in the CYP51 enzyme that are recognized for being involved in M. graminicola populations developing resistance to these fungicides (5,6). Similar mutations in the CYP51 enzyme have also been observed in the clinical setting with Candida albicans and are responsible for azole-resistant infections in patients (7,8).…”

mentioning

confidence: 99%

Novel Substrate Specificity and Temperature-Sensitive Activity of Mycosphaerella graminicola CYP51 Supported by the Native NADPH Cytochrome P450 Reductase

Price

Warrilow

Parker

et al. 2015

Appl Environ Microbiol

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bMycosphaerella graminicola (Zymoseptoria tritici) is an ascomycete filamentous fungus that causes Septoria leaf blotch in wheat crops. In Europe the most widely used fungicides for this major disease are demethylation inhibitors (DMIs). Their target is the essential sterol 14␣-demethylase (CYP51), which requires cytochrome P450 reductase (CPR) as its redox partner for functional activity. The M. graminicola CPR (MgCPR) is able to catalyze the sterol 14␣-demethylation of eburicol and lanosterol when partnered with Candida albicans CYP51 (CaCYP51) and that of eburicol only with M. graminicola CYP51 (MgCYP51). The availability of the functional in vivo redox partner enabled the in vitro catalytic activity of MgCYP51 to be demonstrated for the first time. MgCYP51 50% inhibitory concentration (IC 50 ) studies with epoxiconazole, tebuconazole, triadimenol, and prothioconazole-desthio confirmed that MgCYP51 bound these azole inhibitors tightly. The characterization of the MgCPR/MgCYP51 redox pairing has produced a functional method to evaluate the effects of agricultural azole fungicides, has demonstrated eburicol specificity in the activity observed, and supports the conclusion that prothioconazole is a profungicide. Mycosphaerella graminicola (Zymoseptoria tritici) is an ascomycete filamentous fungus and is the causative pathogen of Septoria leaf blotch in wheat crops. This is the most common cereal crop disease in Europe and can result in devastating losses in crop yield (1, 2). Currently the most widely used fungicides for the control of M. graminicola are demethylase inhibitors (DMIs), which bind to the target cytochrome P450 enzyme, CYP51 (ERG11).CYP51s are ubiquitous in nature and mediate the essential sterol 14␣-demethylation step in the sterol biosynthetic pathway (3). The 14␣-demethylated products are precursors leading to formation of cholesterol (mammals) and ergosterol (fungi) and the formation of a variety of 24-alkylated and desaturated sterols in algae, plants, and protozoa (3). Cholesterol, ergosterol, and sitosterols (plants) play an important structural role in regulating membrane fluidity and permeability of plasma membranes and indirectly modulate the distribution and activity of membrane proteins and ion channels (3, 4). In addition, sterols are precursors of steroid hormones in mammals, brassinosteroids in plants, and ecdysteroids in insects. In yeast and fungi, the CYP51 enzymes are synonymous with lanosterol and eburicol 14␣-demethylation in the production of ergosterol, but as this study shows, M. graminicola CYP51 is able to demethylate only eburicol, in the presence of its native reductase partner, exhibiting novel substrate specificity.The introduction of new azole antifungal compounds has allowed control of M. graminicola infections in wheat to be maintained despite increased tolerance/resistance. The most recently introduced azole is the triazolinethione derivative prothioconazole. However, the control of this disease has been threatened by the identification of mutations in the CYP51 en...

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“…A final mechanism of DMI resistance relies upon "drug" transporters, trans-membrane proteins located in the plasma membranes that utilize ATP to translocate compounds, including toxins, out of the cell, preventing the accumulation of these products to toxic levels, as has been shown for B. cinerea (Leroux and Walker 2011;Leroux et al 2002), M. graminicola ) Penicillium digitatum (Nakaune et al 1998), and possibly V. inaequalis (Koller and Wilcox, 2001). This will be discussed in a later section.…”

Section: Sterol Biosynthesis Inhibitorsmentioning

confidence: 99%

“…To date, most differences identified in fungicide resistance where MDR is implicated have been found to be due to overexpression of ABC transporter genes. Most important to stress is the lack of correlation between expression level specific ABC transporter gene with fungicide resistance, suggesting that multiple transporters may be involved (at least in DMI resistance) or that other mechanisms in addition to upstream transcription factors, have not yet been identified Leroux et al 2011). …”

Section: Mdr-efflux Pumps and Resistancementioning

confidence: 99%

Detection of Fungicide Resistance

Beckerman¹

2013

Fungicides - Showcases of Integrated Plant Disease Management From Around the World

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Multiple mechanisms account for resistance to sterol 14α‐demethylation inhibitors in field isolates of Mycosphaerella graminicola

Abstract: An updated overview of M. graminicola field strains displaying low to high resistance to DMIs is provided here. The management of field resistance and efficacy should be adapted to take these findings into account.

Cited by 188 publications

References 53 publications

Overexpression of ShCYP51B and ShatrD in Sclerotinia homoeocarpa Isolates Exhibiting Practical Field Resistance to a Demethylation Inhibitor Fungicide

Overexpression of ShCYP51B and ShatrD in Sclerotinia homoeocarpa Isolates Exhibiting Practical Field Resistance to a Demethylation Inhibitor Fungicide

Novel Substrate Specificity and Temperature-Sensitive Activity of Mycosphaerella graminicola CYP51 Supported by the Native NADPH Cytochrome P450 Reductase

Detection of Fungicide Resistance

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