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PubMed1990

Azoles and AIDS.

The treatment of opportunistic infections in AIDS patients is changing rapidly as new drugs become available and new studies of old drugs are completed. I have tried to use the AIDS commentaries to keep up with these advances. Since fluconazole has just recently been approved by the US Food and Drug Administration, I asked Dr. Robert A. Larsen, an active clinical investigator at the University of Southern California School of Medicine, to review his current recommendations for the use of the azoles in AIDS patients. The response to therapy of the various mycoses in patients with advanced human immunodeficiency virus (HIV) infection is dramatically different from that in other patient populations and has different end points in each group. Cure is uncommon in HIV-infected patients, and relapsing infection when antifungal therapy is stopped is the rule. Control of infection with relief of symptoms and return to productive, high-quality life is therefore a commendable goal and a reasonable end point. Thus, the azoles, especially fluconazole, are important additions. From the data presented here it appears that amphotericin may still have an edge over fluconazole for acute therapy of cryptococcal meningitis in sicker patients, at least for the first several weeks (although fluconazole may be as good and is certainly less toxic and easier to administer for patients who can take oral medications). Whether 5FC should be added when amphotericin is used for acute therapy is still controversial. Dr. Larsen appears to favor it while my group feels that the potentiation of bone marrow toxicity without any clear evidence of enhanced efficacy in AIDS patients argues against its use.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1999

Comparison of the toxicity of fluconazole and other azole antifungal drugs to murine and human granulocyte-macrophage progenitor cells in vitro.

We studied the inhibitory effects on colony formation by granulocyte-macrophage colony forming units (cfu-gm) of eight azole antifungal agents in vitro. All agents, except fluconazole, inhibited colony formation dose-dependently with 50% inhibitory concentrations (IC50) in the range of 0.78-49 micromol/L in cultures of murine and human bone marrow. For human cells, the IC50 values were 0.553 mg/L for itraconazole, 1.24 mg/L for saperconazole, 2.58 mg/L for clotrimazole, 5.33 mg/L for miconazole, 6.17 mg/L for econazole, 6.27 mg/L for ketoconazole and 8.38 mg/L for oxiconazole. The IC50 of itraconazole for human cfu-gm in vitro was similar to the plasma level of this drug recommended for systemic antifungal therapy (>0.5 mg/L) thus indicating the potential clinical relevance of our data. The IC50 of ketoconazole for human cfu-gm in vitro may be exceeded by plasma levels produced in vivo by high (> or =400 mg) doses, whereas fluconazole failed to reduce colony formation by 50% even at 100 mg/L, a concentration not reached in vivo even after extremely high doses (2000 mg/day). To most of the drugs studied, murine progenitor cells seemed to be less sensitive than the human ones. There was, however, a close correlation between the murine and human log IC50 values of the drugs (r2 = 0.964, P< 0.001), suggesting that cultures of murine bone marrow may be suitable to predict the in-vitro toxicity of azole antifungals to human cfu-gm.

Animals↗
PubMed2006

Identification of promoter elements responsible for the regulation of MDR1 from Candida albicans, a major facilitator transporter involved in azole resistance.

Upregulation of the MDR1 (multidrug resistance 1) gene is involved in the development of resistance to antifungal agents in clinical isolates of the pathogen Candida albicans. To better understand the molecular mechanisms underlying the phenomenon, the cis-acting regulatory elements present in the MDR1 promoter were characterized using a beta-galactosidase reporter system. In an azole-susceptible strain, transcription of this reporter is transiently upregulated in response to either benomyl or H(2)O(2), whereas its expression is constitutively high in an azole-resistant strain (FR2). Two cis-acting regulatory elements within the MDR1 promoter were identified that are necessary and sufficient to confer the same transcriptional responses on a heterologous promoter (CDR2). One, a benomyl response element (BRE), is situated at position -296 to -260 with respect to the ATG start codon. It is required for benomyl-dependent MDR1 upregulation and is also necessary for constitutive high expression of MDR1. A second element, termed H(2)O(2) response element (HRE), is situated at position -561 to -520. The HRE is required for H(2)O(2)-dependent MDR1 upregulation, but dispensable for constitutive high expression. Two potential binding sites (TTAG/CTAA) for the bZip transcription factor Cap1p (Candida AP-1 protein) lie within the HRE. Moreover, inactivation of CAP1 abolished the transient response to H(2)O(2). Cap1p, which has been previously implicated in cellular responses to oxidative stress, may thus play a trans-acting and positive regulatory role in the H(2)O(2)-dependent transcription of MDR1. A minimal BRE (-290 to -273) that is sufficient to detect in vitro sequence-specific binding of protein complexes in crude extracts prepared from C. albicans was also defined. Interestingly, the sequence includes a perfect match to the consensus binding sequence of Mcm1p, raising the possibility that MDR1 may be a direct target of this MADS box transcriptional activator. In conclusion, while the identity of the trans-acting factors that bind to the BRE and HRE remains to be confirmed, the tools developed during this characterization of the cis-acting elements of the MDR1 promoter should now serve to elucidate the nature of the components that modulate its activity.

Antifungal Agents↗
PubMed1992

Azoles, allylamines and drug metabolism.

Four antifungal drugs, the azoles ketoconazole, itraconazole and fluconazole, and the allylamine terbinafine, were studied for their effects on the metabolism of cyclosporin A (CyA) and cortisol by human liver microsomes in vitro (n = 3). Ketoconazole produced marked inhibition of CyA hydroxylase (to metabolites M17 and M1) with IC50 and Ki values of 0.24 +/- 0.01 and 0.022 +/- 0.004 microM, respectively. On the basis of the IC50, itraconazole was 10 times less potent (IC50 of 2.2 +/- 0.2 microM), and fluconazole and terbinafine were each above 100 microM. No kinetic parameters were calculated for terbinafine because of the lack of inhibitory effects. Ketoconazole was the most potent inhibitor of cortisol metabolism (to 6 beta-hydroxycortisol, IC50 = 0.6 microM). Itraconazole produced marked inhibition of cortisol metabolism (IC50 = 2.4 microM), but fluconazole and terbinafine had little effect. These data confirm that ketoconazole is a potent inhibitor of cytochrome P-450-IIIA4, and this has clinical relevance. Although the inhibition with fluconazole was much less than with itraconazole at equimolar concentrations, it should be noted that in-vivo plasma concentrations of fluconazole are much greater than that of itraconazole. Clinical interactions of CyA with both fluconazole and itraconazole have been reported; in contrast to these azoles, terbinafine does not have the same interaction potential.

Antifungal Agents↗
PubMed1990

A comparison of the sterol content of multiple isolates of the Candida albicans Darlington strain with other clinically azole-sensitive and -resistant strains.

The mechanism of azole resistance of Candida albicans NCPF 3310 (the deposited culture of the Darlington strain) has been investigated but never fully explained. Seven isolates of this strain, from various sources, were examined by gas chromatography-mass spectrometry to detect changes in the sterol composition following passage through many laboratories over several years. Five of the seven, including one recently isolated from the patient, were found to be similar to each other in sterol content, containing large amounts of fecosterol. Of the remaining two, one was thought to be a sensitive variant, both produced only small quantities of fecosterol and resembled the normal clinical strains and other azole-resistant strains in sterol content. The sterol composition of the Darlington strain was unique and apparently stable to prolonged in vitro experimentation and passage through the patient.

Azoles↗
PubMed2005

Regulation of azole drug susceptibility by Candida albicans protein kinase CK2.

Fluconazole resistance of the fungal pathogen Candida albicans can arise through several mechanisms, but the responsible genes and pathways are poorly understood. We report here that mutations in CKA2, identified through an insertional mutagenesis screen, confer fluconazole resistance. CKA2 and its homologue CKA1 specify catalytic subunits of protein kinase CK2. Although cka1 mutations have little effect on fluconazole resistance, CKA1 overexpression suppresses the fluconazole resistance of a cka2 mutant. This observation, along with synthetic cka1-cka2 interactions, argues that Cka1p and Cka2p carry out similar functions. cka2 mutants overexpress CDR1 and CDR2, two fluconazole efflux transporter genes, and a cdr1 mutation decreases resistance of a cka2 mutant, as expected if CDR1 and CDR2 overexpression is responsible for fluconazole resistance of the cka2 mutant. The protein phosphatase calcineurin is required for azole tolerance, and we find that the calcineurin inhibitor cyclosporin reverses fluconazole resistance of cka2 mutants. In addition, a mutation in CRZ1, which specifies a homologue of the Saccharomyces cerevisiae transcription factor that is a major target of calcineurin, suppresses fluconazole resistance of cka2 mutants. Expression analysis of Cka2p-responsive genes argues that Cka2p and Crz1p act through distinct mechanisms. Several clinical fluconazole-resistant isolates overexpress some Cka2p-responsive genes. We suggest that a Cka2p-dependent regulatory pathway is altered by clinically derived azole resistance mutations.

Antifungal Agents↗
PubMedDate not supplied

Origin of differences in susceptibility of Candida krusei to azole antifungal agents.

Two Candida krusei isolates were used to compare the effects of fluconazole, ketoconazole and itraconazole on growth and ergosterol synthesis, and to measure intracellular drug contents. Fifty per cent inhibition (IC50) of growth was achieved at 0.05-0.08 microM itraconazole and 0.56-1.2 microM ketoconazole, whereas 91-->100 microM fluconazole was needed to reach the IC50 value. Similar differences in sensitivity to these azole antifungal agents were seen when their effects on ergosterol synthesis from [14C]acetate were measured after 4 h and 24 h of growth. However, when the effects of the azoles on ergosterol synthesis from [14C]mevalonate by subcellular fractions were measured, fluconazole was only 2.3-6.1 times less active than itraconazole, and the IC50 values for ketoconazole were almost similar to those obtained with itraconazole. These results indicate that differences in susceptibility to itraconazole and ketoconazole are unrelated to differences in affinity for the C. krusei cytochrome P450. The much lower growth-inhibitory effects of fluconazole can also be explained partly only by a lower affinity for the P450-dependent 14 alpha-demethylase. The differences in sensitivity of both C. krusei isolates appeared to arise from differences in the intracellular itraconazole, ketoconazole and fluconazole contents. Depending on the experimental conditions, these isolates accumulated 6-41 times more itraconazole than ketoconazole and the intracellular ketoconazole content was 3.0-19.0 times higher than that of fluconazole.

Antifungal Agents↗
PubMed1992

Increased sensitivity of Candida albicans cells accumulating 14 alpha-methylated sterols to active oxygen: possible relevance to in vivo efficacies of azole antifungal agents.

The sensitivity of Candida albicans cells to killing by hydrogen peroxide was found to increase markedly when they were grown in the presence of sub-growth-inhibitory concentrations of the azole drug clotrimazole (CTZ). A superoxide anion-generating system consisting of xanthine and xanthine oxidase also killed such CTZ-treated cells more efficiently than control cells, but this seemed to be accounted for by hydrogen peroxide secondarily formed from superoxide anion as judged by the effect of catalase and superoxide dismutase. The increased sensitivity to hydrogen peroxide was considered to be attributable to the inhibition of 14 alpha-demethylation of ergosterol biosynthesis by CTZ, since a 14 alpha-demethylation-deficient mutant of C. albicans exhibited a similar phenotype. It is suggested that the in vivo efficacy of azole antifungal agents against C. albicans infection is at least partially due to the sensitization of the fungal cells to the oxygen-dependent microbicidal system of the phagocyte.

Antifungal Agents↗
PubMed1995

In vitro activity of a new pneumocandin antifungal agent, L-733,560 against azole-susceptible and -resistant Candida and Torulopsis species.

The activity of a new water-soluble pneumocandin, L-733,560, was evaluated with 107 pathogenic strains of Candida and Torulopsis, which included 23 strains with known multi-azole resistance patterns. In vitro evaluation of L-733,560 activity was performed by a broth microdilution method, and the activity was compared with the activities of amphotericin B, fluconazole, ketoconazole, itraconazole, and flucytosine. The mean MICs of L-733,560 were 0.15 microgram/ml for C. lusitaniae, 0.72 microgram/ml for C. parapsilosis, 0.78 micrograms/ml for C. krusei, and 1.25 micrograms/ml for C. guilliermondii. The results indicate that the new antifungal agent L-733,560 demonstrated the best activity with the lowest MICs against C. albicans, T. glabrata, C. tropicalis, and C. kefyr, less activity against C. krusei, C. lusitaniae, and C. parapsilosis, and the least activity against C. guilliermondii. L-733,560 also demonstrated good activity against the various multi-azole-resistant Candida and T. glabrata isolates.

Anti-Bacterial Agents↗
PubMed1997

Molecular biological characterization of an azole-resistant Candida glabrata isolate.

Two isolates of Candida glabrata, one susceptible and one resistant to azole antifungals, were previously shown to differ in quantity and activity of the cytochrome P-450 14alpha-lanosterol demethylase which is the target for azole antifungals. The resistant isolate also had a lower intracellular level of fluconazole, but not of ketoconazole or itraconazole, than the susceptible isolate. In the present study a 3.7-fold increase in the copy number of the CYP51 gene, encoding the 14alpha-lanosterol demethylase, was found. The amount of CYP51 mRNA transcript in the resistant isolate was eight times greater than it was in the susceptible isolate. Hybridization experiments on chromosomal blots indicated that this increase in copy number was due to duplication of the entire chromosome containing the CYP51 gene. The phenotypic instability of the resistant isolate was demonstrated genotypically: a gradual loss of the duplicated chromosome was seen in successive subcultures of the isolate in fluconazole-free medium and correlated with reversion to susceptibility. The greater abundance of the amplified chromosome induced pronounced differences in the protein patterns of the susceptible and revertant isolates versus that of the resistant isolate, as demonstrated by two-dimensional gel electrophoresis (2D-GE). Densitometry of the 2D-GE product indicated upregulation of at least 25 proteins and downregulation of at least 76 proteins in the resistant isolate.

Antifungal Agents↗
PubMed1997

Modified agar dilution susceptibility testing method for determining in vitro activities of antifungal agents, including azole compounds.

In vitro activities of antifungal agents, including azole compounds, against yeasts were easily determined by using RPMI-1640 agar medium and by incubating the plates in the presence of 20% CO2. The end point of inhibition was clear by this method, even in the case of azole compounds, because of the almost complete inhibition of yeast growth at high concentrations which permitted weak growth of some Candida strains by traditional methods. MICs obtained by the agar dilution method were similar to those obtained by the broth dilution method proposed by the National Committee for Clinical Laboratory Standards.

Antifungal Agents↗
PubMed2004

Proteomic analysis of azole resistance in Candida albicans clinical isolates.

Changes in protein expression within a matched set of Candida albicans isolates representing the acquisition of azole resistance were examined by two-dimensional polyacrylamide gel electrophoresis and peptide mass fingerprinting. Proteins differentially expressed in association with azole resistance included Grp2p, Ifd1p, Ifd4p, Ifd5p, and Erg10p, a protein involved in the ergosterol biosynthesis pathway.

Amino Acids, Sulfur↗
PubMed2005

Differences in interactions between azole drugs related to modifications in the 14-alpha sterol demethylase gene (cyp51A) of Aspergillus fumigatus.

The combined activity of different azole drugs was investigated. Thirty-one Aspergillus fumigatus strains were tested, including two cyp51A(-) and one cyp51B(-) gene-knockout strain and azole-susceptible and -resistant strains with different resistance mechanisms. The combination of itraconazole and voriconazole was synergistic for all strains except for those with gene knockouts.

Antifungal Agents↗
PubMed2005

Genome-wide expression profiling of the response to azole, polyene, echinocandin, and pyrimidine antifungal agents in Candida albicans.

Antifungal agents exert their activity through a variety of mechanisms, some of which are poorly understood. We examined changes in the gene expression profile of Candida albicans following exposure to representatives of the four currently available classes of antifungal agents used in the treatment of systemic fungal infections. Ketoconazole exposure increased expression of genes involved in lipid, fatty acid, and sterol metabolism, including NCP1, MCR1, CYB5, ERG2, ERG3, ERG10, ERG25, ERG251, and that encoding the azole target, ERG11. Ketoconazole also increased expression of several genes associated with azole resistance, including CDR1, CDR2, IFD4, DDR48, and RTA3. Amphotericin B produced changes in the expression of genes involved in small-molecule transport (ENA21), and in cell stress (YHB1, CTA1, AOX1, and SOD2). Also observed was decreased expression of genes involved in ergosterol biosynthesis, including ERG3 and ERG11. Caspofungin produced changes in expression of genes encoding cell wall maintenance proteins, including the beta-1,3-glucan synthase subunit GSL22, as well as PHR1, ECM21, ECM33, and FEN12. Flucytosine increased the expression of proteins involved in purine and pyrimidine biosynthesis, including YNK1, FUR1, and that encoding its target, CDC21. Real-time reverse transcription-PCR was used to confirm microarray results. Genes responding similarly to two or more drugs were also identified. These data shed new light on the effects of these classes of antifungal agents on C. albicans.

Amphotericin B↗
PubMed2005

Targeted gene disruption of the 14-alpha sterol demethylase (cyp51A) in Aspergillus fumigatus and its role in azole drug susceptibility.

The role of Aspergillus fumigatus 14alpha-sterol demethylase (Cyp51A) in azole drug susceptibility was assessed. Targeted disruption of cyp51A in azole-susceptible and -resistant strains decreased MICs from 2- to 40-fold. The cyp51A mutants were morphologically indistinguishable from the wild-type strain, retaining the ability to cause pulmonary disease in neutropenic mice.

Animals↗
PubMed2000

Estimation of minimum sterol 14alpha-demethylation-inhibitory concentration of azoles in Candida yeasts using acetate-mediated growth inhibition: potential utility in susceptibility testing.

We have recently shown that 14alpha-demethylation-deficient cells of Candida albicans are subject to growth arrest by 0.24 M acetate in a yeast extract-peptone-glucose medium and that the minimum concentration of an azole antifungal agent required for total inhibition of sterol 14alpha-demethylation (MDIC for minimum demethylation-inhibitory concentration) is practically identical to its MIC determined in the acetate-supplemented medium (O. Shimokawa and H. Nakayama, Antimicrob. Agents Chemother. 43:100-105, 1999). In the present study we estimated the MDICs of three different azoles (fluconazole, ketoconazole, and itraconazole) for strains of various Candida species using this method and compared them with the MICs determined in the corresponding acetate-free medium. The results demonstrated that the test strains were divided into two classes. One class of strains was characterized by tolerance to 14alpha-demethylation deficiency (MIC > MDIC) and consisted of strains of C. albicans, C. guilliermondii, C. kefyr, and C. tropicalis. The other class was intolerant to 14alpha-demethylation deficiency (MIC approximately MDIC) and comprised strains of C. glabrata, C. krusei, and C. parapsilosis. We also showed that replacement of the yeast extract-peptone-glucose medium with RPMI 1640 medium did not affect the results substantially. Furthermore, the 80% inhibitory concentration (IC(80)) in RPMI 1640 medium, recommended as a substitute for the conventional MIC in susceptibility testing, was found to be close to the MDIC.

Acetates↗
PubMed2004

Modified colorimetric assay for susceptibility testing of azole antifungal drugs against Candida species.

We modified a rapid susceptibility assay (RSA) for antifungal susceptibility testing of azoles based upon glucose utilization. This modified RSA method provides quantitative endpoint readings in 6 h. In this study, the modified RSA and the National Committee for Clinical Laboratory Standards M27-A methods were used to determine the MICs of fluconazole and itraconazole for 118 Candida isolates. Yeast nitrogen base containing 0.12 g of glucose per liter was used for the modified RSA method. For fluconazole, agreement among assays within one or two twofold dilutions was 72.9 and 88.1%, respectively; for itraconazole, agreement within one or two twofold dilutions was 82.2 and 89.8%, respectively. These data suggest that the modified RSA method is a reliable and rapid method for azole antifungal susceptibility testing against Candida species.

Antifungal Agents↗
PubMed2001

Antifungal and immunomodulating activities of 1,4-benzothiazine azole derivatives: review.

We reviewed the studies on the in vitro and in vivo antifungal activity of 1,4-benzothiazine azole derivatives (1,4-BT). A number of different 1,4-BT have been tested for anti-Candida activity, investigating their N-4 substitution, sulfur oxidation state, presence of the carbonyl group in C-3, insertion of the side chain on C-6, C-7 or C-8 of benzothiazine nucleus, the nature of azolic substituent (triazole or imidazole), which tend to differ. Moreover, benzoxazine analogues have been tested to evaluate the effect of sulfur bioisosteric substitution on their activity. We found that their antifungal activity correlates with well-defined chemical characteristics including the presence of ether substitution at the side chain. In fact, ether derivatives are the most active compounds in vivo, although they have little anti-Candida effect in vitro. This discrepancy could be attributed to the fact that 1,4-BT are metabolized to active antifungal compounds and may have in vivo activity through improvement of protective immune response and direct antifungal effects. In fact, 1,4-BT also show immunomodulating activity so that the direct antifungal activity, in combination with the capability to stimulate the immune response, could result in a significant increase in in vivo efficacy.

Animals↗