Article

Morpholine antifungals and their mode of action.

Department of Biochemistry, University College of Wales, Aberystwyth, Dyfed, U.K.
Biochemical Society Transactions (Impact Factor: 2.59). 09/1991; 19(3):788-93.
Source: PubMed
0 Bookmarks
 · 
170 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: During the past three decades azole compounds have been developed as medical and agricultural agents to combat fungal diseases. During the 1980s they were introduced as orally active compounds in medicine and the number of such azole drugs is likely to expand in the near future. They represent a successful strategy for antifungal development, but as the incidence of fungal infection has increased coupled to prolonged use of the drugs, the (almost) inevitable emergence of resistance has occurred. This was after resistance had already been encountered as a serious problem in the field, where a larger number of azole fungicides had been employed commercially. In this review the molecular basis of how azoles work is discussed together with how fungi overcome the inhibitory effect of these compounds: through alterations in the primary target molecule (cytochrome P45051; Erg11p; sterol 14alpha-demethylase); through drug efflux mechanisms and through a suppressor mechanism allowing growth on 14-methylated sterols. Copyright 1999 Harcourt Publishers Ltd.
    Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy 01/2000; 2(6):390-402. · 12.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The two fungicides azoxystrobin and fenpropimorph are used against powdery mildew and rust diseases in wheat (Triticum aestivumL). Azoxystrobin, a strobilurin, inhibits fungal mitochondrial respiration and fenpropimorph, a morpholin, represses biosynthesis of ergosterol, the major sterol of fungal membranes. Although the fungitoxic activity of these compounds is well understood, their effects on plant metabolism remain unclear. In contrast to the fungicides which directly affect pathogen metabolism, benzo(1,2,3) thiadiazole-7-carbothioic acid S-methylester (BTH) induces resistance against wheat pathogens by the activation of systemic acquired resistance in the host plant. In this study, we monitored gene expression in spring wheat after treatment with each of these agrochemicals in a greenhouse trial using a microarray containing 600 barley cDNA clones. Defence-related genes were strongly induced after treatment with BTH, confirming the activation of a similar set of genes as in dicot plants following salicylic acid treatment. A similar gene expression pattern was observed after treatment with fenpropimorph and some defence-related genes were induced by azoxystrobin, demonstrating that these fungicides also activate a defence reaction. However, less intense responses were triggered than with BTH. The same experiments performed under field conditions gave dramatically different results. No gene showed differential expression after treatment and defence genes were already expressed at a high level before application of the agrochemicals. These differences in the expression patterns between the two environments demonstrate the importance of plant growth conditions for testing the impact of agrochemicals on plant metabolism.
    Plant Molecular Biology 04/2005; 57(5):693-707. · 3.52 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The hydroxypyridone ciclopirox olamine belongs to the antimycotic drugs used for the treatment of superficial mycoses. In contrast to the azoles and other antimycotic drugs, its specific mode of action is only poorly understood. To investigate the mode of action of ciclopirox olamine on fungal viability, pathogenicity, and drug resistance, we examined the expression patterns of 47 Candida albicans genes in cells grown in the presence of a subinhibitory concentration (0.6 micro g/ml) of ciclopirox olamine by reverse transcription-PCR. In addition, we used suppression-subtractive hybridization to further identify genes that are up-regulated in the presence of ciclopirox olamine. The expression of essential genes such as ACT1 was not significantly modified in cells exposed to ciclopirox olamine. Most putative and known virulence genes such as genes encoding secreted proteinases or lipases had no or only moderately reduced expression levels. In contrast, exposure of cells to ciclopirox olamine led to a distinct up- or down-regulation of genes encoding iron permeases or transporters (FTR1, FTR2, FTH1), a copper permease (CCC2), an iron reductase (CFL1), and a siderophore transporter (SIT1); these effects resembled those found under iron-limited conditions. Addition of FeCl(3) to ciclopirox olamine-treated cells reversed the effect of the drug. Addition of the iron chelator bipyridine to the growth medium induced similar patterns of expression of distinct iron-regulated genes (FTR1, FTR2). While serum-induced yeast-to-hyphal phase transition of C. albicans was not affected in ciclopirox olamine-treated cells in the presence of subinhibitory conditions, a dramatic increase in sensitivity to oxidative stress was noted, which may indicate the reduced activities of iron-containing gene products responsible for detoxification. Although the Candida drug resistance genes CDR1 and CDR2 were up-regulated, no change in resistance or increased tolerance could be observed even after an incubation period of 6 months. This was in contrast to control experiments with fluconazole, in which the MICs for cells incubated with this drug had noticeably increased after 2 months. These data support the view that the antifungal activity of ciclopirox olamine may at least be partially caused by iron limitation. Furthermore, neither the expression of certain multiple-drug resistance genes nor other resistance mechanisms caused C. albicans resistance to this drug even after long-term exposure.
    Antimicrobial Agents and Chemotherapy 07/2003; 47(6):1805-17. · 4.57 Impact Factor