Resistance to fenarimol in Nectria haematococca var. cucurbitae

Kalamarakis, A. E.; Waard, M.A. de; Ziogas, Basil N.; Georgopoulos, S. G.

doi:10.1016/0048-3575(91)90092-z

Cited by 36 publications

(21 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Similar results have been described for other azole fungicides in Penicillium italicum (De Waard andVan Nistelrooy 1984, 1988) and Nectria haematococca (Kalamarakis et al 1991). Isogenic mutants of A. nidulans strain 003 carrying imaA and imaB genes displayed a relatively low and constant level of accumulation of fungicide over time.…”

Section: Discussionsupporting

confidence: 79%

Multidrug resistance in Aspergillus nidulans involves novel ATP-binding cassette transporters

et al. 1997

View full text Add to dashboard Cite

Two single-copy genes, designated atrA and atrB (ATP-binding cassette transporter A and B), were cloned from the filamentous fungus Aspergillus nidulans and sequenced. Based on the presence of conserved motifs and on hydropathy analysis, the products encoded by atrA and atrB can be regarded as novel members of the ATP-binding cassette (ABC) superfamily of membrane transporters. Both products share the same topology as the ABC transporters PDR5 and SNQ2 from Saccharomyces cerevisiae and CDR1 from Candida albicans, which are involved in multidrug resistance of these yeasts. Significant homology also occurs between the ATP-binding cassettes of AtrA and AtrB, and those of mammalian ABC transporters (P-glycoproteins). The transcription of atrA and, in particular, atrB in mycelium of A. nidulans is strongly enhanced by treatment with several drugs, including antibiotics, azole fungicides and plant defense toxins. The enhanced transcription is detectable within a few minutes after drug treatment and coincides with the beginning of energy-dependent drug efflux activity, reported previously in the fungus for azole fungicides. Transcription of the atr genes has been studied in a wild-type and in a series of isogenic strains carrying the imaA and/or imaB genes, which confer multidrug resistance to various toxic compounds such as the azole fungicide imazalil. atrB is constitutively transcribed at a low level in the wild-type and in strains carrying imaA or imaB. Imazalil treatment enhances transcription of atrB to a similar extent in all strains tested. atrA, unlike atrB, displays a relatively high level of constitutive expression in mutants carrying imaB. Imazalil enhances transcription of atrA more strongly in imaB mutants, suggesting that the imaB locus regulates atrA. Functional analysis demonstrated that cDNA of atrB can complement the drug hypersensitivity associated with PDR5 deficiency in S. cerevisiae.

show abstract

Section: Discussionsupporting

confidence: 79%

Multidrug resistance in Aspergillus nidulans involves novel ATP-binding cassette transporters

et al. 1997

View full text Add to dashboard Cite

show abstract

“…Further evidence in support of this hypothesis is the fact that glucose, a substrate for glycolysis and respiration, produced a decrease in fluconazole accumulation in both susceptible and resistant cells. A similar energy-dependent efflux mechanism has been described in the plant fungal pathogens Penicillium italicum and Nectria haematococca for fenarimol, a pyrimidine ergosterol biosynthesis inhibitor (6,7,14). Uptake was by passive diffusion, and resistant strains showed a greater rate of efflux than susceptible ones.…”

Section: Discussionmentioning

confidence: 88%

Fluconazole resistance due to energy-dependent drug efflux in Candida glabrata

Parkinson

Falconer

Hitchcock

1995

Antimicrob Agents Chemother

113

View full text Add to dashboard Cite

We report on the mechanism of fluconazole resistance in Candida glabrata from a case of infection in which pre-and posttreatment isolates were available for comparison. The resistant, posttreatment isolate was cross-resistant to ketoconazole and itraconazole, in common with other azole-resistant yeasts. Resistance was due to reduced levels of accumulation of [ 3 H]fluconazole rather than to changes at the level of ergosterol biosynthesis. Studies with metabolic or respiratory inhibitors showed that this phenomenon was a consequence of energy-dependent drug efflux, as opposed to a barrier to influx. Since energy-dependent efflux is a characteristic of multidrug resistance in bacteria, yeasts, and mammalian cells, we investigated the possibility that fluconazole resistance is mediated by a multidrug resistance-type mechanism. Benomyl, a substrate for the Candida albicans multidrug resistance protein, showed competition with fluconazole for efflux from resistant C. glabrata isolates, consistent with a common efflux mechanism for these compounds. By contrast, other standard substrates or inhibitors of multidrug resistance proteins had no effect on fluconazole efflux. In conclusion, we have identified energy-dependent efflux of fluconazole, possibly via a multidrug resistance-type transporter, as the mechanism of resistance to fluconazole in C. glabrata.A growing number of debilitated and immunocompromised patients are at risk of serious fungal infections. These include patients receiving cancer therapies and organ transplants and those infected with the virus that causes AIDS. The latter are particularly susceptible to fungal infections because they are permanently immunocompromised, unlike other groups, in whom immunosuppression is transient. Amphotericin B has been the mainstay of therapy for patients with life-threatening mycoses, although nephrotoxicity and administration by slow intravenous infusion are frequent complications (2). The newer azole class of antifungal agents (fluconazole, itraconazole, and ketoconazole) has also proven to be effective in treating invasive mycoses and represents an important alternative to amphotericin B for some indications (for a review, see reference 28).The azole antifungal agents work by inhibiting cytochrome P-450-dependent 14␣-sterol demethylase of ergosterol biosynthesis (P-450 DM ) (for a review, see reference 10). Azoletreated fungi are depleted of ergosterol and accumulate 14␣-methylated sterols which inhibit fungal growth. All of the azoles are fungistatic, as opposed to fungicidal, against Candida spp., underlining the importance of the host's immune system for eradicating the infecting organism and achieving a clinical cure. A corollary of this situation is that AIDS patients require indefinite suppressive therapy, and given the widespread use of fluconazole in end-stage AIDS (including patients who have failed ketoconazole or itraconazole therapy), it is not unexpected that fluconazole-resistant Candida strains have been isolated from this group of patients (22).Stu...

show abstract

“…This frequency is not unique for M. graminicola, since similar frequencies have been observed for other filamentous fungi, e.g., Aspergillus nidulans and Nectria haematococca. Genetic analyses of azoleresistant strains of these organisms identified a polygenic system for azole resistance (22,38). Recently, in Candida glabrata the development of so-called high-frequency azole resistance, which occurred at frequencies (2 ϫ 10 Ϫ4 to 4 ϫ 10 Ϫ4 ) comparable to those in M. graminicola, was described (31).…”

Section: Discussionmentioning

confidence: 99%

ABC Transporters and Azole Susceptibility in Laboratory Strains of the Wheat Pathogen Mycosphaerella graminicola

Zwiers

Stergiopoulos

Nistelrooy

et al. 2002

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Laboratory strains of Mycosphaerella graminicola with decreased susceptibilities to the azole antifungal agent cyproconazole showed a multidrug resistance phenotype by exhibiting cross-resistance to an unrelated chemical, cycloheximide or rhodamine 6G, or both. Decreased azole susceptibility was found to be associated with either decreased or increased levels of accumulation of cyproconazole. No specific relationship could be observed between azole susceptibility and the expression of ATP-binding cassette (ABC) transporter genes MgAtr1 to MgAtr5 and the sterol P450 14␣-demethylase gene, CYP51. ABC transporter MgAtr1 was identified as a determinant in azole susceptibility since heterologous expression of the protein reduced the azole susceptibility of Saccharomyces cerevisiae and disruption of MgAtr1 in one specific M. graminicola laboratory strain with constitutive MgAtr1 overexpression restored the level of susceptibility to cyproconazole to wild-type levels. However, the level of accumulation in the mutant with an MgAtr1 disruption did not revert to the wild-type level. We propose that variations in azole susceptibility in laboratory strains of M. graminicola are mediated by multiple mechanisms.

show abstract

Resistance to fenarimol in Nectria haematococca var. cucurbitae

Cited by 36 publications

References 10 publications

Multidrug resistance in Aspergillus nidulans involves novel ATP-binding cassette transporters

Multidrug resistance in Aspergillus nidulans involves novel ATP-binding cassette transporters

Fluconazole resistance due to energy-dependent drug efflux in Candida glabrata

ABC Transporters and Azole Susceptibility in Laboratory Strains of the Wheat Pathogen Mycosphaerella graminicola

Contact Info

Product

Resources

About