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PubMed2005

Application of proteomic analysis to the study of azole antifungal resistance in Candida albicans.

The sequencing of the Candida albicans genome and recent refinements in protein resolution and identification techniques have greatly enhanced the application of proteomics for the study of this fungal pathogen. Proteome analysis includes the separation and isolation of proteins by two-dimensional polyacrylamide gel electrophoresis and subsequent protein identification by peptide mass fingerprinting using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. This technique has been used for the study of the proteomes of Candida species in the context of virulence, drug response, and resistance. We describe here the application of this approach to the study of azole antifungal resistance in C. albicans.

Antifungal Agents↗
PubMed2005

Emerging azole antifungals.

Systemic and superficial fungal infections have progressively emerged over the past few decades as an increasing cause of human disease, especially in the immunocompromised host. Control of fungal disease has proved difficult because few risk factors are potentially preventable; the population at highest risk for fungal disease, the immunocompromised patient, has been steadily increasing. There is a clear need for additional safe and effective therapeutic agents for the treatment of systemic fungal disease. A new generation of triazoles that includes voriconazole, posaconazole, ravuconazole and albaconazole has emerged and are presently in different phases of clinical investigation. These new triazoles have demonstrated a broad spectrum of activity, in particular against fungal pathogens previously resistant to previously available antifungals. This review highlights the emerging azole antifungals, both those available and in clinical development, and discusses their prospects for the future.

Animals↗
PubMedDate not supplied

[Emerging azole antifungals].

Azoles have maintained a key role in the treatment of invasive fungal infections which have a growing importance, especially in immunocompromised patients. Because of its good activity and safety, fluconazole has becoming the treatment of choice for invasive candidiasis, except those caused by Candida glabrata and C. krusei. In contrast, itraconazole which is active against Aspergillus sp has limited use for the treatment of invasive mould infections due to the high variability of its bioavailibility. Voriconazole is active against a broad range of fungal pathogens including Aspergillus sp and other molds, except Zygomycetes. Voriconazole is used as first-line therapy for invasive aspergillosis and for infections caused by Fusarium and Scedosporium. It is available in both oral and intravenous administration. Posaconazole has similar in vitro activity but currently only the oral form is available. Its main indication is refractory aspergillosis or intolerance to previous treatment. Posaconzole will be very useful for long-term therapy of zygomycetes infections.

Animals↗
PubMed1999

[Present problems and future trend of antifungals for deep seated mycosis. Azole antifungal agents].

Azole antifungal agents are the most common drugs for the treatment of deep seated mycosis throughout the world, because of their favorable anti-fungal spectrum, pharmacokinetics and safety. However there are some weak points in each drug or class, such as emerging resistance or interactions with other drugs. Many new derivatives are now under pre-clinical and clinical evaluation and among them, voriconazole and SCH56592 are showing satisfactory results in their early clinical studies. At the same time, however the ability of doctors to make an appropriate and logical choice for use of these drugs also essential.

Animals↗
PubMed2006

[Studies on the correlation of the method currently used by the Japanese Society for Medical Mycology and its modified method with the NCCLS M27-A2 microdilution method for azole susceptibility testing of Candida species].

To evaluate the currently used Japanese Society for Medical Mycology (JSMM) method for testing the azole susceptibility of yeasts, the activities of fluconazole and itraconazole were tested against recently collected clinical isolates of Candida spp. (n=946) and compared with the National Committee for Clinical Laboratory Standards (NCCLS) M27-A2 microdilution reference method. Favorable correlation with the M27-A2 method was not seen for isolates of C. albicans, C. tropicalis or other Candida spp., particularly their trailing-growth isolates. However, the degree of correlation and agreement of MIC values were markedly improved when testing was performed by the modified JSMM method in which the end-point to be read was changed from IC80 (for the current JSMM method) to IC50. These results suggest that there is an urgent need to revise the current JSMM method.

Azoles↗
PubMedDate not supplied

[Effect of azole derivatives on lucigenin-dependent microsome chemiluminescence].

Both metronidazole and aminotriazole increased while sanazole (drug AK-2123) decreased the NADPH/lucigenin-dependent chemiluminescence of liver microsomes of phenobarbital-treated rats. Sanazole strongly inhibited the lucigenin-dependent chemiluminescence in the enzyme system of xanthine-xanthine oxidase. Aminotriazole and metronidazole were less potent inhibitors of chemiluminescence less than sanazole. All these azole derivatives did not absorb light in the region of light emission of lucigenin. Both lucigenin and sanazole increased the rate of cytochrome c reduction by microsomes in case of using NADPH as a donor of electrons, whereas no effect of metronidazole and aminotriazole on this rate was found. The sanazole inhibition of lucigenin-dependent chemiluminescence could reflect competition between sanazole and lucigenin for electrons in the active centre of flavin reductases. Thus, microsomal NAD(P)H-reductases can be potentially involved in a bioactivation of sanazole. Lucigenin-dependent chemiluminescence cannot be used for measuring the modulating action of agents on reactive oxygen species production in the microsomes, but it may be used for luminometrical studies of enzyme complex NAD(P)H-reductases/cytochrome P450 in model systems.

Acridines↗
PubMed2004

[Activity of the azole drugs in vitro against strains of Candida albicans with different codes isolated from the digestive tract in children].

The activity of ketoconazole (K, R04 1400 molecular weight 531.44), miconazole (M, R01 4889, molecular weight 479.15) and itraconazole (I, R05 1211, molecular weight 705.64) obtained from Janssen Pharmaceutica NV, against Candida albicans strains was studied. The axenic fungal strains were isolated from the faecal samples of children--not previously treated with antifungal drugs--with clinical symptoms suggesting the inflammation of the mucous membrane in the stomach and/or duodenum. The strains were assessed by own methods and unified tests (bioMérieux: API 20 C, API 20 C AUX). Five codes of Candida albicans Berkhout were found. The minimal inhibitory concentration (MIC) values were calculated from 448 dose-response curves according to the agar diffusion--Kadłubowski's method. MICs were also examined by analyzing the variation (min-max, x mean +/- standard error, mode Mo, median Me). It was demonstrated that all the strains used in the study were susceptible to the azoles drugs.

Adolescent↗
PubMed1991

[Quantitative relationships of structure and antimicrobial activity in azole-containing chemotherapeutics].

Several novel azole-containing compounds belonging to condensed heterocycles were studied in vitro within the program of screening antimicrobial substances. Changes in the activity of the compounds against 8 representatives of the microbial genera dependent on the chemical structure were followed up. The changes in the structure referred to the radicals at positions 1 and 3.

Azoles↗
PubMed1990

Effects of novel antifungal azole derivatives on the 5-lipoxygenase and cyclooxygenase pathway.

5-Lipoxygenase and cyclooxygenase catalyze the first steps of the conversion of arachidonic acid into leukotrienes and prostanoids, respectively. Leukotrienes are important mediators of inflammation and thromboxanes are mainly involved in platelet functions. The effects of the new antimycotic drugs, itraconazole and fluconazole, on the 5-lipoxygenase pathway in human polymorphonuclear leukocytes (PMNL), on the eicosanoid metabolism in platelets, platelet aggregation and on cyclooxygenase activity were investigated and compared with miconazole and ketoconazole. Itraconazole inhibited the formation of 5-lipoxygenase metabolites in human PMNL (IC50 = 2 x 10(-6) mol/l), while it had no effect on cyclooxygenase and platelet aggregation at concentrations up to 10(-4) mol/l and 10(-5) mol/l, respectively. Fluconazole was ineffective in all assays. Miconazole inhibited thromboxane synthase (IC50 = 1 x 10(-5) mol/l) and platelet aggregation (IC50 = 3 x 10(-5) mol/l). Ketoconazole was less active in this respect (IC50 for platelet aggregation = 2 x 10(-4) mol/l). All compounds did not affect cyclooxygenase activity in concentrations up to 10(-4) mol/l in the pure enzyme assay. These results indicate that among the tested azoles two compounds show remarkable effects. Miconazole inhibits thromboxane synthesis and itraconazole is a potent inhibitor of leukotriene formation which has only minor effects on the cyclooxygenase pathway. This finding is of considerable interest regarding the application of itraconazole during immunosuppressive therapy and suggests further studies of its potential antiphlogistic properties.

Antifungal Agents↗
PubMed1993

[Synthesis and antifungal activity of 1-(2-[(4-substituted-phenyl) methoxy]-2-(substituted-phenyl) ethyl)-1H-azoles].

Twenty nine 1-(2-[(4-substituted-phenyl) methoxy]-2-(substituted-phenyl) ethyl)-1H-azoles were synthesized for searching of more potent and less toxic antimycotic agents. Nine of the title compounds are first reported. Results of preliminary biological tests showed that most of the title compounds exhibited activity against the common pathogenic fungi such as Candida albicans, Microsporum bodin, Trichophyton gypsum, Epidermophyton floccosum, Trichophyton violaceum, Microsporum ferrugincum, Trichophyton rubrum and Microsporum gypsum. The antifungal activity of compound 14 was roughly comparable to clotrimazole and econazole against Candida albicans, but was more active against other test fungi than clotrimazole and econazole. Compounds 4, 5, 6, 12, 23 also have good antifungal activity, but are less active against Candida albicans.

Antifungal Agents↗
PubMed1993

A preliminary study of in vitro antibiotic activity of saperconazole and other azoles on Paracoccidioides brasiliensis.

Saperconazole, a new triazole related to itraconazole, was tested against Paracoccidioides brasiliensis and results compared with ketoconazole and itraconazole. The fungus was highly sensitive to the action of these compounds, particularly saperconazole, with minimum inhibitory concentrations and minimum fungicidal concentrations ranging from 10(-7) to 10(-10) M (equivalent to 6.7 x 10(-2)-6.7 x 10(-5) micrograms ml-1 for saperconazole), according to the morphological phase and the antifungal tested. The yeast phase was more sensitive than the mycelial phase to any of the azoles. Morphological changes were observed in the cell membranes, particularly when saperconazole was used as the antifungal agent.

Antifungal Agents↗
PubMed1996

Selective calmodulin antagonists fail to inhibit phorbol ester-induced superoxide anion release from human neutrophils: effects of antifungal azole derivatives.

The ability of antifungal azole derivatives to inhibit superoxide anion release from human leucocytes and the relevance of their documented calmodulin (CaM) antagonism was investigated with respect to anti-inflammatory drug activity. Econazole, miconazole and clotrimazole were found to inhibit phorbol ester-induced release of superoxide anions from human polymorphonuclear leucocytes effectively with IC50 values in the range of 36-162 mumol/l. In contrast, bifonazole and ketoconazole produced minimal or no inhibition, thus suggesting that mechanisms other than inhibition of superoxide anion release may largely account for their clinical activity in inflammatory skin disorders. The selective CaM antagonist J-8, which was used as a reference, failed to inhibit the release process, whereas W-7 as a dual CaM/protein kinase C inhibitor induced dose-dependent inhibition. When tested on protein kinase C activity in vitro, econazole, miconazole and clotrimazole were inhibitory, but bifonazole and ketoconazole were without significant effect. It is thus concluded that inhibition of superoxide anion release reflects the ability of these drugs to inhibit protein kinase C, but not their potency to antagonize CaM. Given the role of reactive oxygen species in tissue damage by neutrophils, we propose protein kinase C, rather than CaM, as another potential target of anti-inflammatory therapy.

Animals↗
PubMed1996

Antifungal screening of seven new azole derivatives.

Two strains of the dermatophyte Epidermophyton floccosum were treated with seven new synthetic azole derivatives to determine their possible antifungal activity. Among these, two diazopyrazoles (1-phenyl-3-methyl-4-diazo-5-methanesulphonamid and 1,3-dimethyl-4-diazo-5-methanesulphonamid) and the triazole (4-methyl-6-t-butylpyrazolo[3,4-d] [1,2,3]triazole) were inactive at the highest dose tested (100 micrograms/ml). The 4-methyl-6-phenyl-pyrazolo[3,4-d] [1,2,3]triazole produced only a partial inhibition of growth, whereas the most active compounds were the two thiadiazines (6H-3-phenyl-5-methyl-7-(3,4-dichlorophenyl)pyrazolo[3,4-c] [1,2,5]thiadiazine-2,2-dioxide and 7-methyl-2-phenyl-4H-pyrazolo[1,5-c] [1,3,5]thiadiazine-4-one), and an aminoisoxazole (3-methyl-5-aminoisoxazole-4-thiocyanate), which induced a remarkable and sometimes complete reduction in the growth rate of the fungus. The structure-activity relationships are discussed.

Antifungal Agents↗
PubMedDate not supplied

New evidence that Candida albicans possesses additional ATP-binding cassette MDR-like genes: implications for antifungal azole resistance.

Emergence of resistance of Candida albicans to antifungal triazoles is increasingly recognized as an important cause of refractory mucosal candidiasis in HIV-infected patients. Recently, CDR1, which is thought to be analogous to the human MDR-1 P-glycoprotein, has been cloned in C. albicans. It has been proposed that its expression is partially responsible for fluconazole resistance in C. albicans. This gene is characterized by the presence of an ATP binding cassette (ABC) region and is distinct from the BENr gene which does not encode such a functional domain. As the molecular basis for fluconazole resistance appears to be multifactorial, we considered that there may be other ATP binding cassette-containing MDR genes that may potentially contribute to antifungal azole resistance in C. albicans. We therefore sought to identify potential target sequences that may be derived from candidate genes that share homology with the ATP binding cassette region of the human MDR-1 P-glycoprotein. Degenerate oligonucleotide primers based on the known sequence from the ATP binding cassette region of the human MDR-1 P-glycoprotein were used to amplify PCR products within the range of 100 bp in length from C. albicans isolates (3 fluconazole-susceptible and 3 fluconazole-resistant). Sequence analysis of individually subcloned PCR products, derived from the six isolates revealed 34 sequences in total. The results of our study identified 14 clones (with at least one per isolate) with a high degree of homology to the ATP binding cassette of the human MDR-1 P-glycoprotein. The BLAST search did not disclose homology of these new sequences to the C. albicans CDR1 gene, suggesting that C. albicans may possess more than one MDR-like gene. We conclude that C. albicans may possess one or more additional genes encoding ATP binding cassette MDR-like proteins that are distinct from CDR 1 and which could participate in the development of fluconazole resistance.

AIDS-Related Opportunistic Infections↗
PubMed2006

Reaction of azole heterocycles with tris(dimethylamino)borane, a new method for the construction of tripodal borate-centred ligands.

Reaction of 2-mercapto-1-methylimidazole (methimazole) with tris(dimethylamino)borane, B(NMe2)3, provides the tetrahedral dimethylamine adduct of tris(methimazolyl)borane, [(Me2HN)B(methimazolyl)3]. By contrast, imidazole, 2-methylimidazole, 2-chloroimidazole and benzimidazole provide the homoleptic tetra-azolyl systems H[B(azolyl)4], and the same product is obtained even when a substoichiometric quantity of the heterocyle is employed. The change in reaction outcome is correlated with the variation of basic pKa for the heterocycles. A simple acid-base reaction with elimination of HNMe2 is proposed for the reaction with the weakly basic, but more strongly acidic, methimazole. However, for the more strongly basic imidazoles, initial coordination of the heterocycle imine nitrogen to the weakly Lewis acidic boron centre in B(NMe2)3 to form the tetrahedral adduct [(azole)B(NMe2)3] is proposed. The greater availability of the NMe2 lone pairs in this species results in increased basicity and a rapid reaction with further heterocycle to provide the observed H[B(azolyl)4] products. For 2-nitroimidazole, the low basicity (and increased N-H acidity) results in the formation of [(HNMe2)B(2-nitroimidazolyl)3] on reaction with B(NMe2)3, analogous to the product formed with methimazole. Both [(HNMe2)B(methimazolyl)3] and H[B(benzimidazolyl)4] have been structurally characterised by single crystal X-ray crystallography. This chemistry has been exploited to provide a new synthesis of borate-centred tripod ligands, whereby N-methylimidazole is used to activate B(NMe2)3 to reaction with methimazole to form the new ligand [(N-methylimidazole)B(methimazolyl)3] in good yield and a complex of this ligand with Ru(II) has been structurally characterised.

Journal Article↗
PubMed2007

Iridium(I) pyridyl azolate complexes with saturated red metal-to-ligand charge transfer phosphorescence; fundamental and potential applications in organic light-emitting diodes.

Preparation of a new series of neutral metal complexes [(cod)Ir(fppz)] (1), [(cod)Ir(bppz)] (2), [(cod)Ir(fptz)] (3) and [(cod)Ir(bptz)] (4), bearing one cod ligand and a pyridyl azolate chelate are reported. A single-crystal X-ray diffraction study of 3 reveals the expected distorted square-planar geometry. The lowest absorption band consists of IrI atom increased triplet dpi-->pi* transitions (3MLCT), the assignment of which is firmly supported by the theoretical approaches. Complexes 1-4 exhibit weak phosphorescence in degassed solution at room temperature, whereas much more intense, solid-state phosphorescence appears in the range 622-649 nm. The pure MLCT emission was used as a prototypical model to address its remarkable spectral differences from the IrIII isoquinoline pyrrolide complex (5), which has mainly 3pipi phosphorescence. Complex 3 was used as a dopant to fabricate red-emitting phosphorescent organic light-emitting diodes (OLEDs). For the 7 % doped device, a maximum brightness of 3010 cd m-2 was achieved at an applied voltage of 15 V and with CIE coordinates of (0.56, 0.33), demonstrating for the first time the potential of neutral IrI complexes in OLED applications.

Journal Article↗
PubMed1996

Midazolam hydroxylation by human liver microsomes in vitro: inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents.

Biotransformation of the imidazobenzodiazepine midazolam to its alpha-hydroxy and 4-hydroxy metabolites was studied in vitro using human liver microsomal preparations. Formation of alpha-hydroxy-midazolam was a high-affinity (Km = 3.3 mumol/L) Michaelis-Menten process coupled with substrate inhibition at high concentrations of midazolam. Formation of 4-hydroxy-midazolam had much lower apparent affinity (57 mumol/L), with minimal evidence of substrate inhibition. Based on comparison of Vmax/Km ratios for the two pathways, alpha-hydroxy-midazolam formation was estimated to account for 95% of net intrinsic clearance. Three azole antifungal agents were inhibitors of midazolam metabolism in vitro, with inhibition being largely consistent with a competitive mechanism. Mean competitive inhibition constants (Ki) versus alpha-hydroxy-midazolam formation were 0.0037 mumol/L for ketoconazole, 0.27 mumol/L for itraconazole, and 1.27 mumol/L for fluconazole. An in vitro-in vivo scaling model predicted inhibition of oral midazolam clearance due to coadministration of ketoconazole or itraconazole; the predicted inhibition was consistent with observed interactions in clinical pharmacokinetic studies. The selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine and its principal metabolite, norfluoxetine, also were inhibitors of both pathways of midazolam biotransformation, with norfluoxetine being a much more potent inhibitor than was fluoxetine itself. This finding is consistent with results of other in vitro studies and of clinical studies, indicating that fluoxetine, largely via its metabolite norfluoxetine, may impair clearance of P450-3A substrates.

Anesthetics, Intravenous↗
PubMed1995

Resistance to azole drugs in Neurospora crassa.

Neurospora crassa was susceptible to azole drugs: ketoconazole (MIC 1 microgram/ml), fluconazole (MIC 5 micrograms/ml), and SCH39304 (MIC 5 micrograms/ml). Mutants of N. crassa resistant to ketoconazole were selected and genetically characterized. The seven characterized resistance mutations represented at least four genetic loci. Some mutants, but not all, were also resistant to fluconazole and to SCH39304.

Antifungal Agents↗