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PubMed2006

The role of echinocandins, extended-spectrum azoles, and polyenes to treat opportunistic moulds and Candida.

Three classes of antifungals--polyenes, extended-spectrum azoles, and echinocandins--are now available for treating systemic fungal infections. Guidance for the appropriate use of this expanded variety of antifungals may come from recent clinical trials. Extended-spectrum azoles have excellent in vitro activity against Aspergillus and have been shown to improve clinical outcomes. For Zygomycetes, along with the lipid formulations of amphotericin, of the new agents, only posaconazole has activity. For Candida, the echinocandins offer a broad spectrum of activity. These new agents offer less toxicity and potentially improved efficacy in these difficult infections.

Journal Article↗
PubMed2006

Endogenous endophthalmitis with azole-resistant Candida albicans--Case report and review of the literature.

Candida endophthalmitis accounts for the majority of fungal endophthalmitis. Despite its clinical relevance there are no controlled trials on different treatment regimens. We report a case of endogenous endophthalmitis caused by azole-resistant Candida albicans following abdominal surgery in an otherwise healthy woman, and review the literature concerning treatment recommendations. In consideration of the serious outcome with loss of sight in insufficiently treated endophthalmitis we like to increase awareness to this disease entity and the possibility of azole-resistance, even in treatment-naive patients.

Antifungal Agents↗
PubMed1992

Inhibition by a novel azole antifungal agent with a geranyl group on lanosterol 14 alpha-demethylase of yeast.

AFK-108 (1-[2-(2,4-dichlorophenyl)-2-((2E)-3,7-dimethylocta-2,6- dienyloxy)ethyl]-1H-imidazole) is a new imidazole derivative characterized by a geranyl substituent showing strong antifungal activity. Azole antifungal agents are known to be potent inhibitors of lanosterol 14 alpha-demethylase (P450(14)DM) of fungi. The role of the geranyl group of AFK-108 on interaction of AFK-108 with the target was studied by using Saccharomyces cerevisiae P450(14)DM as the model enzyme. AFK-108 and some of its derivatives bound to oxidized P450(14)DM with one-to-one stoichiometry and inhibited the demethylase activity. AFK-108 derivatives having the longer farnesyl or the shorter prenyl group showed lower affinity than AFK-108 for the enzyme. AFK-108 caused 100% inhibition at the equivalent concentration to P450(14)DM in the reaction mixture (0.07 microM), while the farnesyl derivative inhibited the activity by 60% at the same concentration. AFK-108 interfered with the binding of CO to the ferrous P450(14)DM. However, the interfering effect of the prenyl derivative was lower than that of AFK-108. Another AFK-108 derivative having the saturated 3,7-dimethyloctyl group was also a weaker inhibitor than AFK-108. These experiments suggest that the geranyl group of AFK-108 interacts with the substrate binding site of P450(14)DM that recognises the side chain of the substrate. AFK-108 is the first example of an azole derivative interacting with the side chain recognising region of the substrate binding site of P450(14)DM.

Antifungal Agents↗
PubMed1991

The antioxidant action of ketoconazole and related azoles: comparison with tamoxifen and cholesterol.

The azole antifungal drug ketoconazole was found to inhibit Fe(III)-ascorbate dependent lipid peroxidation using either rat liver microsomes or ox-brain phospholipid liposomes as the substrate. It also inhibited microsomal peroxidation induced by the Fe(III)-ADP/NADPH system. The related azoles, miconazole and clotrimazole, were much weaker inhibitors than ketoconazole. Ketoconazole was approximately equipotent with the triphenylethylene anticancer drug tamoxifen in the microsomal system and was almost as effective as 4-hydroxytamoxifen in the liposomal system. Ketoconazole introduced into phospholipid liposomes during their preparation inhibited Fe(III)-ascorbate induced lipid peroxidation to a greater extent than similarly introduced cholesterol, ergosterol or tamoxifen. Miconazole and clotrimazole were again poor inhibitors of lipid peroxidation in this system. These antioxidant effects of ketoconazole may be due to membrane stabilization in the systems used. The implications of our findings for the clinical applications of these drugs are discussed.

Animals↗
PubMed1992

The effects of the antifungal azoles itraconazole, fluconazole, ketoconazole and miconazole on cytokine gene expression in human lymphoid cells.

The antifungal azole drugs itraconazole (itra; R51,211), fluconazole (flu; UK-49,858), ketoconazole (keto) and micronazole (mico) have been investigated for their suppressive influence on the gene expression of the immunoregulatory cytokines IL2, IL4, IL9, GM-CSF, TNF-alpha, IFN-gamma, as well as both chains of the IL2 receptor in human PBMC and of the cytokines in the human keratinocyte cell line HaCat 17.5. The results obtained in Northern blot analysis were compared with the effects of the established immunosuppressant drug CSA and the new immunosuppressive drug FK 506, as well as the cytokine TGF-beta, which is also immunosuppressive. While 1 microgram/ml CSA and 0.1 microgram/ml FK 506 completely suppressed PHA-stimulated accumulation of mRNA for IL2, IL4, IL9, GM-CSF, TNF-alpha and IFN-gamma in PBMC, flu, keto and TGF-beta failed to inhibit any (except TNF-alpha blocked by TGF-beta). Itra and mico did suppress accumulation of mRNA, but unlike CSA and FK 506, only at high doses (10 micrograms/ml) and after extended incubation (24 h). None of the drugs nor TGF-beta suppressed the expression of the IL2R-alpha and IL2R-beta genes or TNF-alpha-stimulated cytokine gene expression in keratinocytes. Itra and mico, 1 mg/ml (achievable serum level), caused only slight inhibition of the cytokines in PBMC after 6 and 24 h of incubation. These results demonstrate that the mode of action of the azoles is different from CSA and FK 506.(ABSTRACT TRUNCATED AT 250 WORDS)

Antifungal Agents↗
PubMed2006

Combination of caspofungin and an azole or an amphotericin B formulation in invasive fungal infections.

OBJECTIVES: Combination of caspofungin and another anti-fungal agent raise expectation of improved efficacy in severe fungal infections including failures to first line therapy. METHODS: We assessed the efficacy and safety of a combination therapy including caspofungin in 17 immunosuppressed or postoperative patients progressive despite standard anti-fungal therapy. RESULTS: The infections included aspergillosis (6), invasive candidiasis (9), mucormycosis (1) and Scedosporium pneumonia (1). Infections had failed one to four prior lines of treatment. The anti-fungal agent combined to caspofungin was either an amphotericin B formulation or an azole. There were 12 favourable responses (71%) and five failures. The survival rate at 3 months was 47%. Eleven patients died within 2-533 days. The causes of death included the initial fungal infection (4), relapse of the infection after switching to oral monotherapy (2), breakthrough aspergillosis (1), and the underlying condition (4). Clinical and renal tolerance were good. Significant hepatic abnormalities were recorded in eight (50%) of the 16 patients evaluable for biological tolerance. CONCLUSION: Caspofungin combined with an azole or with amphotericin B may be of interest in the treatment of serious fungal infections after failure of conventional therapy. Close monitoring of hepatic function is required. These approach should be evaluated in prospective trials.

Adolescent↗
PubMed1998

Role of the new azoles in the treatment of fungal osteoarticular infections.

OBJECTIVES: To analyze the usefulness of the new azoles for the treatment of fungal osteoarticular infections, and to report three cases of fungal knee arthritis treated with fluconazole in our unit. METHODS: The medical literature was reviewed for all cases of osteoarticular infection caused by fungi and treated with fluconazole or itraconazole registered in the MedLine Silver Platter database from 1972 to 1997. RESULTS: The total number of patients included in this review was 56; 19 were treated with fluconazole and 37 with itraconazole. The most frequent causative agents implicated were fungi of the genuses Candida and Aspergillus. There were eight therapeutic failures, and there were no statistically different findings among the patients in terms of their health status. Adverse effects were unusual. CONCLUSIONS: Controlled studies are necessary to establish the true role of the new azole drugs in the treatment of fungal osteoarticular infections, but they seem to be a promising therapeutic option.

Adult↗
PubMed2002

Mannan changes induced by 3-methyl-5-aminoisoxazole-4-thiocyanate, a new azole derivative, on Epidermophyton floccosum.

The antifungal activity of 3-methyl-5-aminoisoxazole-4-thiocyanate, a new azole derivative, was studied on the dermatophyte Epidermophyton floccosum. The compound strongly inhibited the in vitro growth of two different strains of the fungus and even induced profound morphogenetic anomalies. Optical and electron microscopy showed that such treatment targets the endomembrane system, particularly the plasmalemma, causing abnormal extrusion of the wall mannans. This results in improper arrangement of the different parietal materials; the walls are thus weak and subject to subapical rupture which terminates cell growth and elongation of the hypha. The morphological results and the preliminary biochemical data on fungal sterols suggest that this compound employs an action mechanism similar to that of other azoles used in therapy.

Antifungal Agents↗
PubMed1998

Multiple resistance mechanisms to azole antifungals in yeast clinical isolates.

The use of antifungal agents, especially the azole class, has increased in parallel with a higher incidence of fungal infections, particularly in immunocompromised patients. This situation has favored the appearance of Candida species, prominent among them C. albicans and C. globrata, with acquired resistance to these agents. This review focuses on the latest developments in investigations of molecular mechanisms contributing to azole resistance. Multiple resistance mechanisms have been described that can coexist in resistant clinical isolates. Understanding resistance mechanisms is of value not only for the design of new antifungal agents but also the development of strategies of overcome or delay the emergence of resistance.

Journal Article↗
PubMed2006

Surface plasmon resonance analysis of antifungal azoles binding to CYP3A4 with kinetic resolution of multiple binding orientations.

The heme-containing cytochrome P450s (CYPs) are a major enzymatic determinant of drug clearance and drug-drug interactions. The CYP3A4 isoform is inhibited by antifungal imidazoles or triazoles, which form low-spin heme iron complexes via formation of a nitrogen-ferric iron coordinate bond. However, CYP3A4 also slowly oxidizes the antifungal itraconazole (ITZ) at a site that is approximately 25 A from the triazole nitrogens, suggesting that large antifungal azoles can adopt multiple orientations within the CYP3A4 active site. Here, we report a surface plasmon resonance (SPR) analysis with kinetic resolution of two binding modes of ITZ, and the related drug ketoconazole (KTZ). SPR reveals a very slow off-rate for one binding orientation. Multiphasic binding kinetics are observed, and one of the two binding components resolved by curve fitting exhibits "equilibrium overshoot". Preloading of CYP3A4 with the heme ligand imidazole abolishes this component of the antifungal azole binding trajectories, and it eliminates the conspicuously slow off-rate. The fractional populations of CYP3A4 complexes corresponding to different drug orientations can be manipulated by altering the duration of the pulse of drug exposure. UV-vis difference absorbance titrations yield low-spin spectra and K(D) values that are consistent with the high-affinity complex resolved by SPR. These results demonstrate that ITZ and KTZ bind in multiple orientations, including a catalytically productive mode and a slowly dissociating inhibitory mode. Most importantly, they provide the first example of a SPR-based method for the kinetic characterization of binding of a drug to any human CYP, including mechanistic insight not available from other methods.

Antifungal Agents↗
PubMed2005

Effect of 2-(2-Pyridyl)azole-based ancillary ligands (L1-4) on the electrophilicity of the nitrosyl function in [RuII(trpy)(L1-)4)(NO)]3+ [trpy = 2,2':6',2' '-Terpyridine]. synthesis, structures, and spectroscopic, electrochemical, and kinetic aspects.

Ruthenium nitrosyl complexes [Ru(trpy)(L(1-4))(NO)](3+) (13-16) [trpy = 2,2':6',2' '-terpyridine, L(1) = 2-(2-pyridyl)benzoxazole, L(2) = 2-(2-pyridyl)benzthiazole, L(3) = 2-(2-pyridyl)benzimidazole, L(4) = 1-methyl-2-(2-pyridyl)-1H-benzimidazole] were obtained in a stepwise manner starting from [Ru(II)(trpy)(L(1-4))(Cl)]ClO(4) (1-4) -->[Ru(II)(trpy)(L(1-4))(H(2)O)](ClO(4))(2) (5-8) --> [Ru(II)(trpy)(L(1-4)) (NO(2))]ClO(4) (9-12) --> [Ru(II)(trpy)(L(1,2,4))(NO)](ClO(4))(3) (13, 14, 16)/[Ru(II)(trpy)(L(3))(NO)](ClO(4))(2)(NO(3)) (15). Crystal structures of 1, 2, 4, 9, 12, 13, 15, and 16 established the stereoretentive nature of the transformation processes. Though the complexes of L(1), L(3), and L(4) were isolated in the isomeric form A (pi-acceptor trpy and azole ring in the equatorial plane and the pyridine and chloride donors in the axial positions), complexes of L(2) preferentially stabilized in form B (trpy and pyridine in the equatorial plane and the azole ring and chloride donors in the axial positions). The nu(NO) stretching frequency varied in the range of 1957-1932 cm(-1), 13 >> 14 approximately 15 > 16, primarily depending on the electronic aspects of L as well as the isomeric structural forms. The coordinated nitrosyl function underwent successive reductions of [Ru(II)-NO(+)](3+) --> [Ru(II)-NO(*)](2+) and [Ru(II)-NO(*)](2+) --> [Ru(II)-NO(-)](+), and the first reduction potential follows the order 14 > 13 >> 15 approximately 16. The nearly axial EPR spectra having nitrogen hyperfine splittings (A approximately 26 G) at 77 K of 13(-)-16(-) with g approximately 2.0 established that the reduction process is largely centered around the nitrosyl function. Despite an appreciably high nu(NO), the complexes were found to be unusually stable even in the aqueous medium. They transformed slowly and only partially into the corresponding nitro derivatives in H(2)O (k approximately 10(-4) s(-1) and K = 0.4-3.8). The chloro (1-4), aqua (5-8), and nitro (9-12) derivatives displayed reasonably strong emissions near 700 nm at 77 K (phi = 10(-1)-10(-2)). The aqua derivative 7 was found to interact with the calf thymus and the circular form of p-Bluescript SK DNA.

Journal Article↗
PubMed2003

Structure-based de novo design, synthesis, and biological evaluation of non-azole inhibitors specific for lanosterol 14alpha-demethylase of fungi.

The active site of lanosterol 14alpha-demethylase (CYP51) was investigated via MCSS functional group mapping and LUDI calculations. Several non-azole lead molecules were obtained by coupling structure-based de novo design with chemical synthesis and biological evaluation. All of the lead molecules exhibited a strong inhibitory effect on CYP51 of Candida albicans. They occupy the substrate-binding site and interfere with the binding of azole antifungal agents in a competitive manner. The mode of action of the lead molecules was validated by spectrophotomeric analysis and SAR studies. This is the first successful example reported for the inhibitor design of the cytochrome P450 superfamily using the de novo design strategy. Because the affinity of the lead molecules for CYP51 was mainly attributed to their nonbonding interaction with the apoprotein, the studies presented here afford the opportunity to develop novel antifungal agents that specifically interact with the residues in the active site and avoid the serious toxicity arising from coordination binding with the heme of mammalian P450s.

Antifungal Agents↗
PubMed2004

Design and synthesis of aryl diphenolic azoles as potent and selective estrogen receptor-beta ligands.

New diphenolic azoles as highly selective estrogen receptor-beta agonists are reported. The more potent and selective analogues of these series have comparable binding affinities for ERbeta as the natural ligand 17beta-estradiol but are >100-fold selective over ERalpha. Our design strategy not only followed a traditional SAR approach but also was supported by X-ray structures of ERbeta cocrystallized with various ligands as well as molecular modeling studies. These strategies enabled us to take advantage of a single conservative residue substitution in the ligand-binding pocket, ERalpha Met(421) --> ERbeta Ile(373), to optimize ERbeta selectivity. The 7-position-substituted benzoxazoles (Table 5) were the most selective ligands of both azole series, with ERB-041 (117) being >200-fold selective for ERbeta. The majority of ERbeta selective agonists tested that were at least approximately 50-fold selective displayed a consistent in vivo profile: they were inactive in several models of classic estrogen action (uterotrophic, osteopenia, and vasomotor instability models) and yet were active in the HLA-B27 transgenic rat model of inflammatory bowel disease. These data suggest that ERbeta-selective agonists are devoid of classic estrogenic effects and may offer a novel therapy to treat certain inflammatory conditions.

Androgen Antagonists↗
PubMed2006

Catalytic C-H arylation of SEM-protected azoles with palladium complexes of NHCs and phosphines.

[reaction: see text] The synthesis and catalytic evaluation of palladium complexes containing imidazolyl carbene ligand of varying steric and electronic properties is reported. These complexes catalyze the efficient C-H arylation of SEM-protected azole heteroarenes and thus provide a good method for preparation of a wide range of arylated free (NH)-azoles including pyrroles, indoles, imidazoles, and imidazo[1,2-a]pyridines. The reaction is operationally simple; the complexes are insensitive to moisture.

Journal Article↗
PubMed1999

Pre-emptive therapy with azoles in lung transplant patients. Geneva Lung Transplantation Group.

Pulmonary fungal infection is diagnosed in up to 15-25% of lung transplant recipients and frequently bears a fatal outcome. This prospective uncontrolled study addresses the efficacy and safety of pre-emptive azole therapy against fungal infection in these patients. Fluconazole or itraconazole have been systematically used according to reported fungus sensitivity after the discovery of fungi in lower respiratory tract samples. Patients were treated until the bronchial suture was normal and the cultures of the following bronchoscopy remained negative. Fungi were found post-transplantation in the lower respiratory tract specimens of 26 out of 31 (84%) patients, predominantly Candida albicans (20 patients) and Aspergillus fumigatus (16 patients). Mycelia characteristic of Candida spp. or Aspergillus spp. were found in necrotic tissue at the bronchial suture of nine patients. The mean duration of the 38 treatments was 3.6+/-2.6 months (range, 0.5-12 months). After a median follow-up of 16 (range, 0-48) months, two cases of extended ulcerative and pseudo membranous Aspergillus fumigatus bronchitis were observed and healed under itraconazole treatment. In conclusion, pre-emptive azole therapy may be effective and well-tolerated in lung transplant patients where fungi are found in the airways or pleura.

Adult↗
PubMed2001

Crystal structure of cytochrome P450 14alpha -sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors.

Cytochrome P450 14alpha-sterol demethylases (CYP51) are essential enzymes in sterol biosynthesis in eukaryotes. CYP51 removes the 14alpha-methyl group from sterol precursors such as lanosterol, obtusifoliol, dihydrolanosterol, and 24(28)-methylene-24,25-dihydrolanosterol. Inhibitors of CYP51 include triazole antifungal agents fluconazole and itraconazole, drugs used in treatment of topical and systemic mycoses. The 2.1- and 2.2-A crystal structures reported here for 4-phenylimidazole- and fluconazole-bound CYP51 from Mycobacterium tuberculosis (MTCYP51) are the first structures of an authentic P450 drug target. MTCYP51 exhibits the P450 fold with the exception of two striking differences-a bent I helix and an open conformation of BC loop-that define an active site-access channel running along the heme plane perpendicular to the direction observed for the substrate entry in P450BM3. Although a channel analogous to that in P450BM3 is evident also in MTCYP51, it is not open at the surface. The presence of two different channels, with one being open to the surface, suggests the possibility of conformationally regulated substrate-in/product-out openings in CYP51. Mapping mutations identified in Candida albicans azole-resistant isolates indicates that azole resistance in fungi develops in protein regions involved in orchestrating passage of CYP51 through different conformational stages along the catalytic cycle rather than in residues directly contacting fluconazole. These new structures provide a basis for rational design of new, more efficacious antifungal agents as well as insight into the molecular mechanism of P450 catalysis.

Amino Acid Sequence↗
PubMed1997

Characterization of Saccharomyces cerevisiae CYP61, sterol delta22-desaturase, and inhibition by azole antifungal agents.

Cytochrome P-45061 (CYP61) was a cytochrome P-450 revealed during the yeast genome project when chromosome XIII was sequenced. Here we report on the properties of this second microsomal P-450 of vegetatively growing yeast. The enzyme kinetics associated with its endogenous role in sterol Delta22-desaturation revealed a Km of 20.4 microM and a Vmax of 2.9nmol/min/nmol CYP61. The affinity of the enzyme for antifungal drugs was characterized to investigate its potential role in determining tolerance to these sterol 14alpha-demethylase (CYP51) inhibitors. Drug binding induced a type II spectral change, which became saturated at equimolar concentrations of azole drug and P-450. Fluconazole exhibited slightly reduced affinity in comparison to ketoconazole as indicated by carbon monoxide displacement. These and Ki determination for fluconazole (0.14 nM) revealed CYP61 to have a similar affinity to azole drugs when compared with data available for CYP51, and the implications for antifungal treatment were considered.

Antifungal Agents↗
PubMed1983

In-vitro studies of a new oral azole antimycotic, BAY N 7133.

The in-vitro antifungal activities of BAY N 7133, a new orally absorbed synthetic azole derivative against 364 strains of fungal pathogens were studied in direct comparison with another orally active azole compound ketoconazole, using an agar dilution procedure. BAY N 7133 was found to have a broad spectrum of antifungal activity and to inhibit most pathogenic yeasts and fungi at concentrations ranging from less than or equal to 0.04 to 10 mg/1, with the exception only of some strains of zygomycetic pathogens. It was equal to or even greater than ketoconazole in activity against most of the fungal pathogens tested. Composition and pH of culture media and inoculum size altered the effect of BAY N 7133. No in-vitro development of drug resistance was demonstrated. BAY N 7133 can be considered to have a possible usefulness in the treatment of human mycoses.

Antifungal Agents↗