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Sample records for azole antifungal agents

  1. Current and Emerging Azole Antifungal Agents

    PubMed Central

    Sheehan, Daniel J.; Hitchcock, Christopher A.; Sibley, Carol M.

    1999-01-01

    Major developments in research into the azole class of antifungal agents during the 1990s have provided expanded options for the treatment of many opportunistic and endemic fungal infections. Fluconazole and itraconazole have proved to be safer than both amphotericin B and ketoconazole. Despite these advances, serious fungal infections remain difficult to treat, and resistance to the available drugs is emerging. This review describes present and future uses of the currently available azole antifungal agents in the treatment of systemic and superficial fungal infections and provides a brief overview of the current status of in vitro susceptibility testing and the growing problem of clinical resistance to the azoles. Use of the currently available azoles in combination with other antifungal agents with different mechanisms of action is likely to provide enhanced efficacy. Detailed information on some of the second-generation triazoles being developed to provide extended coverage of opportunistic, endemic, and emerging fungal pathogens, as well as those in which resistance to older agents is becoming problematic, is provided. PMID:9880474

  2. Azole antifungal agents: emphasis on new triazoles.

    PubMed Central

    Saag, M S; Dismukes, W E

    1988-01-01

    Many advances have been made in antifungal therapy over the last three decades. Itraconazole and fluconazole, two investigational triazole agents, are the most recent additions to the list of antifungal drugs. This review has focused primarily on their mechanisms of action, favorable pharmacologic properties, and spectra of activity against a broad range of systemic pathogens. Itraconazole and fluconazole show much promise as orally active agents, with less potential for toxicity than the currently available azoles. Fluconazole and, to a lesser degree, itraconazole are especially promising therapies for cryptococcal meningitis. In addition, fluconazole may prove to be highly effective in urinary tract infections caused by Candida species and other fungi. Ongoing and future clinical trials will more clearly define the specific roles of itraconazole and fluconazole in the treatment of systemic mycoses. PMID:2831809

  3. Management of drug and food interactions with azole antifungal agents in transplant recipients.

    PubMed

    Dodds-Ashley, Elizabeth

    2010-08-01

    Azole antifungal agents are frequently used in hematopoietic stem cell and solid organ transplant recipients for prevention or treatment of invasive fungal infections. However, because of metabolism by or substrate activity for various isoenzymes of the cytochrome P450 system and/or P-glycoprotein, azole antifungals have the potential to interact with many of the drugs commonly used in these patient populations. Thus, to identify drug interactions that may result between azole antifungals and other drugs, we conducted a literature search of the MEDLINE database (1966-December 2009) for English-language articles on drug interaction studies involving the azole antifungal agents fluconazole, itraconazole, voriconazole, and posaconazole. Another literature search between each of the azoles and the immunosuppressants cyclosporine, tacrolimus, and sirolimus, as well as the corticosteroids methylprednisolone, dexamethasone, prednisolone, and prednisone, was also conducted. Concomitant administration of azoles and immunosuppressive agents may cause clinically significant drug interactions resulting in extreme immunosuppression or toxicity. The magnitude and duration of an interaction between azoles and immunosuppressants are not class effects of the azoles, but differ between drug combinations and are subject to interpatient variability. Drug interactions in the transplant recipient receiving azole therapy may also occur with antibiotics, chemotherapeutic agents, and acid-suppressive therapies, among other drugs. Initiation of an azole antifungal in transplant recipients nearly ensures a drug-drug interaction, but often these drugs are required. Management of these interactions first involves knowledge of the potential drug interaction, appropriate dosage adjustments when necessary, and therapeutic or clinical monitoring at an appropriate point in therapy to assess the drug-drug interaction (e.g., immunosuppressive drug concentrations, signs and symptoms of toxicity

  4. Antifungal activities of azole agents against the Malassezia species.

    PubMed

    Miranda, Karla Carvalho; de Araujo, Crystiane Rodrigues; Costa, Carolina Rodrigues; Passos, Xisto Sena; de Fátima Lisboa Fernandes, Orionalda; do Rosário Rodrigues Silva, Maria

    2007-03-01

    In this paper, we identified 95 Malassezia isolates by morphological and biochemical criteria and assessed the in vitro activity of fluconazole, itraconazole, ketoconazole and voriconazole by broth microdilution against these species using slightly modified Leeming-Notman medium. The Malassezia isolates were identified as M. furfur (74), M. sympodialis (11), M. obtusa (8) and M. globosa (2). The modified Leeming-Notman medium used for susceptibility testing allowed good growth of Malassezia spp. Visual reading of the minimal inhibitory concentration (MIC) was readily achieved until Day 5 of incubation at 32 degrees C. Although high MIC values of 16 microg/mL for fluconazole were observed in 9.5% of Malassezia isolates, in general these microorganisms were susceptible to all drugs studied. Interestingly, one M. globosa isolate showed high MIC values for voriconazole, itraconazole and fluconazole. For the 95 strains, the MIC ranges were <0.03-4 microg/mL for ketoconazole, <0.03 to >16 microg/mL for voriconazole, <0.125 to >64 microg/mL for fluconazole and <0.03-16 microg/mL for itraconazole. In summary, the good reproducibility and visual readings obtained using modified Leeming-Notman medium suggest that this medium should be proposed for antifungal testing of drugs against Malassezia spp.

  5. Antifungal drug resistance to azoles and polyenes.

    PubMed

    Masiá Canuto, Mar; Gutiérrez Rodero, Félix

    2002-09-01

    There is an increased awareness of the morbidity and mortality associated with fungal infections caused by resistant fungi in various groups of patients. Epidemiological studies have identified risk factors associated with antifungal drug resistance. Selection pressure due to the continuous exposure to azoles seems to have an essential role in developing resistance to fluconazole in Candida species. Haematological malignancies, especially acute leukaemia with severe and prolonged neutropenia, seem to be the main risk factors for acquiring deep-seated mycosis caused by resistant filamentous fungi, such us Fusarium species, Scedosporium prolificans, and Aspergillus terreus. The still unacceptably high mortality rate associated with some resistant mycosis indicates that alternatives to existing therapeutic options are needed. Potential measures to overcome antifungal resistance ranges from the development of new drugs with better antifungal activity to improving current therapeutic strategies with the present antifungal agents. Among the new antifungal drugs, inhibitors of beta glucan synthesis and second-generation azole and triazole derivatives have characteristics that render them potentially suitable agents against some resistant fungi. Other strategies including the use of high doses of lipid formulations of amphotericin B, combination therapy, and adjunctive immune therapy with cytokines are under investigation. In addition, antifungal control programmes to prevent extensive and inappropriate use of antifungals may be needed.

  6. Amino Acid Substitutions in the Cytochrome P-450 Lanosterol 14α-Demethylase (CYP51A1) from Azole-Resistant Candida albicans Clinical Isolates Contribute to Resistance to Azole Antifungal Agents

    PubMed Central

    Sanglard, Dominique; Ischer, Françoise; Koymans, Luc; Bille, Jacques

    1998-01-01

    The cytochrome P-450 lanosterol 14α-demethylase (CYP51A1) of yeasts is involved in an important step in the biosynthesis of ergosterol. Since CYP51A1 is the target of azole antifungal agents, this enzyme is potentially prone to alterations leading to resistance to these agents. Among them, a decrease in the affinity of CYP51A1 for these agents is possible. We showed in a group of Candida albicans isolates from AIDS patients that multidrug efflux transporters were playing an important role in the resistance of C. albicans to azole antifungal agents, but without excluding the involvement of other factors (D. Sanglard, K. Kuchler, F. Ischer, J.-L. Pagani, M. Monod, and J. Bille, Antimicrob. Agents Chemother. 39:2378–2386, 1995). We therefore analyzed in closer detail changes in the affinity of CYP51A1 for azole antifungal agents. A strategy consisting of functional expression in Saccharomyces cerevisiae of the C. albicans CYP51A1 genes of sequential clinical isolates from patients was designed. This selection, which was coupled with a test of susceptibility to the azole derivatives fluconazole, ketoconazole, and itraconazole, enabled the detection of mutations in different cloned CYP51A1 genes, whose products are potentially affected in their affinity for azole derivatives. This selection enabled the detection of five different mutations in the cloned CYP51A1 genes which correlated with the occurrence of azole resistance in clinical C. albicans isolates. These mutations were as follows: replacement of the glycine at position 129 with alanine (G129A), Y132H, S405F, G464S, and R467K. While the S405F mutation was found as a single amino acid substitution in a CYP51A1 gene from an azole-resistant yeast, other mutations were found simultaneously in individual CYP51A1 genes, i.e., R467K with G464S, S405F with Y132H, G129A with G464S, and R467K with G464S and Y132H. Site-directed mutagenesis of a wild-type CYP51A1 gene was performed to estimate the effect of each of these

  7. Overview of medically important antifungal azole derivatives.

    PubMed Central

    Fromtling, R A

    1988-01-01

    Fungal infections are a major burden to the health and welfare of modern humans. They range from simply cosmetic, non-life-threatening skin infections to severe, systemic infections that may lead to significant debilitation or death. The selection of chemotherapeutic agents useful for the treatment of fungal infections is small. In this overview, a major chemical group with antifungal activity, the azole derivatives, is examined. Included are historical and state of the art information on the in vitro activity, experimental in vivo activity, mode of action, pharmacokinetics, clinical studies, and uses and adverse reactions of imidazoles currently marketed (clotrimazole, miconazole, econazole, ketoconazole, bifonazole, butoconazole, croconazole, fenticonazole, isoconazole, oxiconazole, sulconazole, and tioconazole) and under development (aliconazole and omoconazole), as well as triazoles currently marketed (terconazole) and under development (fluconazole, itraconazole, vibunazole, alteconazole, and ICI 195,739). PMID:3069196

  8. Susceptibility of clinical isolates of Candida spp. to terconazole and other azole antifungal agents.

    PubMed

    Pfaller, M A; Gerarden, T

    1989-01-01

    Terconazole is a triazole ketal derivative with potent, broad-spectrum antifungal activity. We investigated the in vitro activity of terconazole, miconazole, and clotrimazole, against 94 clinical isolates of Candida spp.: C. albicans (n = 68), C. tropicalis (n = 18), and C. parapsilosis (n = 8). In vitro susceptibility testing was performed using a broth microdilution method. The minimal inhibitory concentrations of terconazole were less than those of miconazole against C. albicans and C. parapsilosis but higher against C. tropicalis. Terconazole was more active than clotrimazole against C. parapsilosis and less active against C. albicans and C. tropicalis. Terconazole inhibited the uptake of 14C-labeled glucose, leucine, and hypoxanthine into C. albicans and caused the rapid release of intracellular K+. Based on these studies, terconazole has promising anticandidal activity and warrants further in vitro and in vivo investigation.

  9. Effects of terconazole and other azole antifungal agents on the sterol and carbohydrate composition of Candida albicans.

    PubMed

    Pfaller, M A; Riley, J; Koerner, T

    1990-01-01

    The effects of terconazole, a triazole antifungal, on the sterol and carbohydrate composition of Candida albicans was compared with that of three imidazoles: clotrimazole, miconazole, and butoconazole. Exposure of C. albicans to terconazole resulted in a profound depletion of ergosterol with a corresponding increase in lanosterol content versus control cells. Carbohydrate analysis revealed a significant (245%) increase in chitin and a minimal effect on glucan and mannan in terconazole-treated cells. Similar effects on sterol and carbohydrate composition were observed with clotrimazole and miconazole. Butoconazole had a similar effect on sterol composition but had no effect on carbohydrate composition. The decreased ergosterol and increased lanosterol content is consistent with 14 alpha-demethylase inhibition by terconazole and the other azoles. The increase in cell wall chitin is most likely due to deregulation of chitin synthesis secondary to ergosterol depletion in the cell membrane. Because both chitin and ergosterol are critical components of the fungal cell, perturbation of the production and localization of these components by terconazole is likely to contribute to the selective toxicity of this compound for C. albicans and other fungi.

  10. Biochemical approaches to selective antifungal activity. Focus on azole antifungals.

    PubMed

    Vanden Bossche, H; Marichal, P; Gorrens, J; Coene, M C; Willemsens, G; Bellens, D; Roels, I; Moereels, H; Janssen, P A

    1989-01-01

    Azole antifungals (e.g. the imidazoles: miconazole, clotrimazole, bifonazole, imazalil, ketoconazole, and the triazoles: diniconazole, triadimenol, propiconazole, fluconazole and itraconazole) inhibit in fungal cells the 14 alpha-demethylation of lanosterol or 24-methylenedihydrolanosterol. The consequent inhibition of ergosterol synthesis originates from binding of the unsubstituted nitrogen (N-3 or N-4) of their imidazole or triazole moiety to the heme iron and from binding of their N-1 substituent to the apoprotein of a cytochrome P-450 (P-450(14)DM) of the endoplasmic reticulum. Great differences in both potency and selectivity are found between the different azole antifungals. For example, after 16h of growth of Candida albicans in medium supplemented with [14C]-acetate and increasing concentrations of itraconazole, 100% inhibition of ergosterol synthesis is achieved at 3 x 10(-8) M. Complete inhibition of this synthesis by fluconazole is obtained at 10(-5) M only. The agrochemical imidazole derivative, imazalil, shows high selectivity, it has almost 80 and 98 times more affinity for the Candida P-450(s) than for those of the piglet testes microsomes and bovine adrenal mitochondria, respectively. However, the topically active imidazole antifungal, bifonazole, has the highest affinity for P-450(s) of the testicular microsomes. The triazole antifungal itraconazole inhibits at 10(-5) M the P-450-dependent aromatase by 17.9, whereas 50% inhibition of this enzyme is obtained at about 7.5 x 10(-6)M of the bistriazole derivative fluconazole. The overall results show that both the affinity for the fungal P-450(14)DM and the selectivity are determined by the nitrogen heterocycle and the hydrophobic N-1 substituent of the azole antifungals. The latter has certainly a greater impact. The presence of a triazole and a long hypdrophobic nonligating portion form the basis for itraconazole's potency and selectivity.

  11. Chloroquine sensitizes biofilms of Candida albicans to antifungal azoles.

    PubMed

    Shinde, Ravikumar Bapurao; Raut, Jayant Shankar; Chauhan, Nitin Mahendra; Karuppayil, Sankunny Mohan

    2013-01-01

    Biofilms formed by Candida albicans, a human pathogen, are known to be resistant to different antifungal agents. Novel strategies to combat the biofilm associated Candida infections like multiple drug therapy are being explored. In this study, potential of chloroquine to be a partner drug in combination with four antifungal agents, namely fluconazole, voriconazole, amphotericin B, and caspofungin, was explored against biofilms of C. albicans. Activity of various concentrations of chloroquine in combination with a particular antifungal drug was analyzed in a checkerboard format. Growth of biofilm in presence of drugs was analyzed by XTT-assay, in terms of relative metabolic activity compared to that of drug free control. Results obtained by XTT-metabolic assay were confirmed by scanning electron microscopy. The interactions between chloroquine and four antifungal drugs were determined by calculating fractional inhibitory concentration indices. Azole resistance in biofilms was reverted significantly (p<0.05) in presence of 250μg/mL of chloroquine, which resulted in inhibition of biofilms at very low concentrations of antifungal drugs. No significant alteration in the sensitivity of biofilms to caspofungin and amphotericin B was evident in combination with chloroquine. This study for the first time indicates that chloroquine potentiates anti-biofilm activity of fluconazole and voriconazole.

  12. Candida tropicalis Antifungal Cross-Resistance Is Related to Different Azole Target (Erg11p) Modifications

    PubMed Central

    Forastiero, A.; Mesa-Arango, A. C.; Alastruey-Izquierdo, A.; Alcazar-Fuoli, L.; Bernal-Martinez, L.; Pelaez, T.; Lopez, J. F.; Grimalt, J. O.; Gomez-Lopez, A.; Cuesta, I.; Zaragoza, O.

    2013-01-01

    Candida tropicalis ranks between third and fourth among Candida species most commonly isolated from clinical specimens. Invasive candidiasis and candidemia are treated with amphotericin B or echinocandins as first-line therapy, with extended-spectrum triazoles as acceptable alternatives. Candida tropicalis is usually susceptible to all antifungal agents, although several azole drug-resistant clinical isolates are being reported. However, C. tropicalis resistant to amphotericin B is uncommon, and only a few strains have reliably demonstrated a high level of resistance to this agent. The resistance mechanisms operating in C. tropicalis strains isolated from clinical samples showing resistance to azole drugs alone or with amphotericin B cross-resistance were elucidated. Antifungal drug resistance was related to mutations of the azole target (Erg11p) with or without alterations of the ergosterol biosynthesis pathway. The antifungal drug resistance shown in vitro correlated very well with the results obtained in vivo using the model host Galleria mellonella. Using this panel of strains, the G. mellonella model system was validated as a simple, nonmammalian minihost model that can be used to study in vitro-in vivo correlation of antifungals in C. tropicalis. The development in C. tropicalis of antifungal drug resistance with different mechanisms during antifungal treatment has potential clinical impact and deserves specific prospective studies. PMID:23877676

  13. New generation azole antifungals in clinical investigation.

    PubMed

    Girmenia, Corrado

    2009-09-01

    Considerable progress in treating systemic mycoses has been achieved in the past years through development of new drugs in association with more advanced diagnostic procedures. Here, we review the pharmacological, microbiological and clinical development progress with the so-called 'second generation' triazoles: voriconazole, posaconazole, ravuconazole, isavuconazole and albaconazole. All these drugs exhibit a favourable pharmacokinetic and toxicity profile and possess high activity against resistant and emerging pathogens. However, only voriconazole and posaconazole have been adequately investigated in Phase III studies and have been approved by the regulatory agencies in the treatment and prophylaxis of invasive fungal infections, respectively. On the contrary, ravuconazole, isavuconazole and albaconazole have not been investigated in adequate clinical trials and, in the absence of proper data, the real possibilities of these agents as competitors for the treatment and prevention of invasive mycoses in the clinical setting are still unknown. The drug interactions and the variability in the absorption and/or metabolism of the triazoles, in particular voriconazole and posaconazole, may determine an unpredictable exposure of the pathogens to the antifungal treatments. Literature evidences strongly support the use of therapeutic drug monitoring for these triazoles which may be crucial for the proper management of severe invasive fungal infections.

  14. Azole Antifungal Resistance in Candida albicans and Emerging Non-albicans Candida Species

    PubMed Central

    Whaley, Sarah G.; Berkow, Elizabeth L.; Rybak, Jeffrey M.; Nishimoto, Andrew T.; Barker, Katherine S.; Rogers, P. David

    2017-01-01

    Within the limited antifungal armamentarium, the azole antifungals are the most frequent class used to treat Candida infections. Azole antifungals such as fluconazole are often preferred treatment for many Candida infections as they are inexpensive, exhibit limited toxicity, and are available for oral administration. There is, however, extensive documentation of intrinsic and developed resistance to azole antifungals among several Candida species. As the frequency of azole resistant Candida isolates in the clinical setting increases, it is essential to elucidate the mechanisms of such resistance in order to both preserve and improve upon the azole class of antifungals for the treatment of Candida infections. This review examines azole resistance in infections caused by C. albicans as well as the emerging non-albicans Candida species C. parapsilosis, C. tropicalis, C. krusei, and C. glabrata and in particular, describes the current understanding of molecular basis of azole resistance in these fungal species. PMID:28127295

  15. Inhibition of the enzymatic activity of heme oxygenases by azole-based antifungal drugs.

    PubMed

    Kinobe, Robert T; Dercho, Ryan A; Vlahakis, Jason Z; Brien, James F; Szarek, Walter A; Nakatsu, Kanji

    2006-10-01

    Ketoconazole (KTZ) and other azole antifungal agents are known to have a variety of actions beyond the inhibition of sterol synthesis in fungi. These drugs share structural features with a series of novel heme oxygenase (HO) inhibitors designed in our laboratory. Accordingly, we hypothesized that therapeutically used azole-based antifungal drugs are effective HO inhibitors. Using gas chromatography to quantify carbon monoxide formation in vitro and in vivo, we have shown that azole-containing antifungal drugs are potent HO inhibitors. Terconazole, sulconazole, and KTZ were the most potent drugs with IC(50) values of 0.41 +/- 0.01, 1.1 +/- 0.4, and 0.3 +/- 0.1 microM for rat spleen microsomal HO activity, respectively. Kinetic characterization revealed that KTZ was a noncompetitive HO inhibitor. In the presence of KTZ (2.5 and 10 microM), K(m) values for both rat spleen and brain microsomal HO were not altered; however, a significant decrease in the catalytic capacity (V(max)) was observed (P < 0.005). KTZ was also found to weakly inhibit nitric-oxide synthase with an IC(50) of 177 +/- 2 microM but had no effect on the enzymatic activity of NADPH cytochrome P450 reductase. Because these drugs were effective within the concentration range observed in humans, it is possible that inhibition of HO may play a role in some of the pharmacological actions of these antimycotic drugs.

  16. Inhibition of human CYP19 by azoles used as antifungal agents and aromatase inhibitors, using a new LC-MS/MS method for the analysis of estradiol product formation.

    PubMed

    Trösken, Eva R; Fischer, Kathrin; Völkel, Wolfgang; Lutz, Werner K

    2006-02-15

    Azoles are used as fungicides in agriculture or antifungal drugs in medicine. Their therapeutic activity is based on the inhibition of fungal lanosterol-14alpha-demethylase (CYP51). Azoles are also used for the treatment of estrogen-dependent diseases, e.g. in breast cancer therapy. Inhibition of CYP19 (aromatase) is the working principle for tumor therapy, but is an unwanted side effect of azoles used as fungicides or antifungal drugs. The inhibition of recombinant human CYP19 by 21 azoles in use for the three different purposes was investigated using the natural substrate testosterone. Estradiol product formation was measured by a newly developed and fully validated analytical method based on liquid chromatography-tandem mass spectrometry utilizing photospray ionization (APPI). Potency of enzyme inhibition was expressed in terms of IC50 concentrations. The two cytostatic drugs fadrozole and letrozole were the most potent inhibitors. However, azoles used as fungicides, e.g. prochloraz, or as antifungal drugs, e.g. bifonazole, were almost as potent inhibitors of aromatase as the drugs used in tumor therapy. Comparison of plasma concentrations that may be reached in antifungal therapy do not allow for large safety factors for bifonazole and miconazole. The IC50 values were compared to data obtained with other substrates, such as the pseudo-substrate dibenzylfluorescein (DBF). A high correlation was found, indicating that the fluorescence assay with DBF can well be used for potency ranking and screening of chemicals for aromatase inhibition. The data for antifungal drugs show that side effects on steroid hormone synthesis in humans due to inhibition of aromatase should be considered.

  17. Structural Basis of Human CYP51 Inhibition by Antifungal Azoles

    SciTech Connect

    Strushkevich, Natallia; Usanov, Sergey A.; Park, Hee-Won

    2010-09-22

    The obligatory step in sterol biosynthesis in eukaryotes is demethylation of sterol precursors at the C14-position, which is catalyzed by CYP51 (sterol 14-alpha demethylase) in three sequential reactions. In mammals, the final product of the pathway is cholesterol, while important intermediates, meiosis-activating sterols, are produced by CYP51. Three crystal structures of human CYP51, ligand-free and complexed with antifungal drugs ketoconazole and econazole, were determined, allowing analysis of the molecular basis for functional conservation within the CYP51 family. Azole binding occurs mostly through hydrophobic interactions with conservative residues of the active site. The substantial conformational changes in the B{prime} helix and F-G loop regions are induced upon ligand binding, consistent with the membrane nature of the protein and its substrate. The access channel is typical for mammalian sterol-metabolizing P450 enzymes, but is different from that observed in Mycobacterium tuberculosis CYP51. Comparison of the azole-bound structures provides insight into the relative binding affinities of human and bacterial P450 enzymes to ketoconazole and fluconazole, which can be useful for the rational design of antifungal compounds and specific modulators of human CYP51.

  18. The Hsp90 Co-chaperones Sti1, Aha1, and P23 Regulate Adaptive Responses to Antifungal Azoles

    PubMed Central

    Gu, Xiaokui; Xue, Wei; Yin, Yajing; Liu, Hongwei; Li, Shaojie; Sun, Xianyun

    2016-01-01

    Heat Shock Protein 90 (Hsp90) is essential for tumor progression in humans and drug resistance in fungi. However, the roles of its many co-chaperones in antifungal resistance are unknown. In this study, by susceptibility test of Neurospora crassa mutants lacking each of 18 Hsp90/Calcineurin system member genes (including 8 Hsp90 co-chaperone genes) to antifungal drugs and other stresses, we demonstrate that the Hsp90 co-chaperones Sti1 (Hop1 in yeast), Aha1, and P23 (Sba1 in yeast) were required for the basal resistance to antifungal azoles and heat stress. Deletion of any of them resulted in hypersensitivity to azoles and heat. Liquid chromatography–mass spectrometry (LC-MS) analysis showed that the toxic sterols eburicol and 14α-methyl-3,6-diol were significantly accumulated in the sti1 and p23 deletion mutants after ketoconazole treatment, which has been shown before to led to cell membrane stress. At the transcriptional level, Aha1, Sti1, and P23 positively regulate responses to ketoconazole stress by erg11 and erg6, key genes in the ergosterol biosynthetic pathway. Aha1, Sti1, and P23 are highly conserved in fungi, and sti1 and p23 deletion also increased the susceptibility to azoles in Fusarium verticillioides. These results indicate that Hsp90-cochaperones Aha1, Sti1, and P23 are critical for the basal azole resistance and could be potential targets for developing new antifungal agents. PMID:27761133

  19. Newer antifungal agents.

    PubMed

    Türel, Ozden

    2011-03-01

    The frequency and spectrum of fungal infections have been increasing steadily over the last several decades. The reason for this increase may be explained by the increase in the number of immunocompromised patients due to malignancies, AIDS, invasive surgical procedures and transplantation. In parallel with this increase, several therapeutic options have become available but problems such as intrinsic or acquired antifungal resistance have led researchers to develop new antifungal drugs with expanded effectiveness. Reduced toxicity, enhancement of bioavailability and counteraction of resistance are features desired by clinicians. The aim of this article is to summarize the studies involving isavuconazole, ravuconazole, albaconazole, aminocandin and some other investigational antifungal agents. Most data on the clinical use of ravuconazole, isavuconazole and albaconazole are mainly available as meeting abstracts or limited to animal studies or Phase I/II studies in humans. These new antifungal agents in development offer extended half-lives, possibly reduced drug interaction profiles and good tolerance. In addition to activity against Candida and Aspergillus spp., they have a broad spectrum of activity including activity against resistant and emerging pathogens. The real possibilities of these agents will only be fully understood after adequate randomized clinical trials.

  20. Genesis of Azole Antifungal Resistance from Agriculture to Clinical Settings.

    PubMed

    Azevedo, Maria-Manuel; Faria-Ramos, Isabel; Cruz, Luísa Costa; Pina-Vaz, Cidália; Rodrigues, Acácio Gonçalves

    2015-09-02

    Azole fungal resistance is becoming a major public health problem in medicine in recent years. However, it was known in agriculture since several decades; the extensive use of these compounds results in contamination of air, plants, and soil. The increasing frequency of life-threatening fungal infections and the increase of prophylactical use of azoles in high-risk patients, taken together with the evolutionary biology evidence that drug selection pressure is an important factor for the emergence and spread of drug resistance, can result in a dramatic scenario. This study reviews the azole use in agricultural and medical contexts and discusses the hypothetical link between its extensive use and the emergence of azole resistance among human fungal pathogens.

  1. Chiral profiling of azole antifungals in municipal wastewater and recipient rivers of the Pearl River Delta, China.

    PubMed

    Huang, Qiuxin; Wang, Zhifang; Wang, Chunwei; Peng, Xianzhi

    2013-12-01

    Enantiomeric compositions and fractions (EFs) of three chiral imidazole (econazole, ketoconazole, and miconazole) and one chiral triazole (tebuconazole) antifungals were investigated in wastewater, river water, and bed sediment of the Pearl River Delta, South China. The imidazole pharmaceuticals in the untreated wastewater were racemic to weakly nonracemic (EFs of 0.450-0.530) and showed weak enantioselectivity during treatment in the sewage treatment plant. The EFs of the dissolved azole antifungals were usually different from those of the sorbed azoles in the suspended particulate matter, suggesting different behaviors for the enantiomers of the chiral azole antifungals in the dissolved and particulate phases of the wastewater. The azole antifungals were widely present in the rivers. The bed sediment was a sink for the imidazole antifungals. The imidazoles were prevalently racemic, whereas tebuconazole was widely nonracemic in the rivers. Seasonal effects were observed on distribution and chirality of the azole antifungals. Concentrations of the azole antifungals in the river water were relatively higher in winter than in spring and summer while the EF of miconazole in the river water was higher in summer. The mechanism of enantiomeric behavior of the chiral azole antifungals in the environment warrants further research.

  2. Azole Antifungal Agents To Treat the Human Pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through Inhibition of Sterol 14α-Demethylase (CYP51).

    PubMed

    Lamb, David C; Warrilow, Andrew G S; Rolley, Nicola J; Parker, Josie E; Nes, W David; Smith, Stephen N; Kelly, Diane E; Kelly, Steven L

    2015-08-01

    In this study, we investigate the amebicidal activities of the pharmaceutical triazole CYP51 inhibitors fluconazole, itraconazole, and voriconazole against Acanthamoeba castellanii and Acanthamoeba polyphaga and assess their potential as therapeutic agents against Acanthamoeba infections in humans. Amebicidal activities of the triazoles were assessed by in vitro minimum inhibition concentration (MIC) determinations using trophozoites of A. castellanii and A. polyphaga. In addition, triazole effectiveness was assessed by ligand binding studies and inhibition of CYP51 activity of purified A. castellanii CYP51 (AcCYP51) that was heterologously expressed in Escherichia coli. Itraconazole and voriconazole bound tightly to AcCYP51 (dissociation constant [Kd] of 10 and 13 nM), whereas fluconazole bound weakly (Kd of 2,137 nM). Both itraconazole and voriconazole were confirmed to be strong inhibitors of AcCYP51 activity (50% inhibitory concentrations [IC50] of 0.23 and 0.39 μM), whereas inhibition by fluconazole was weak (IC50, 30 μM). However, itraconazole was 8- to 16-fold less effective (MIC, 16 mg/liter) at inhibiting A. polyphaga and A. castellanii cell proliferation than voriconazole (MIC, 1 to 2 mg/liter), while fluconazole did not inhibit Acanthamoeba cell division (MIC, >64 mg/liter) in vitro. Voriconazole was an effective inhibitor of trophozoite proliferation for A. castellanii and A. polyphaga; therefore, it should be evaluated in trials versus itraconazole for controlling Acanthamoeba infections.

  3. Azole Antifungal Agents To Treat the Human Pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through Inhibition of Sterol 14α-Demethylase (CYP51)

    PubMed Central

    Lamb, David C.; Warrilow, Andrew G. S.; Rolley, Nicola J.; Parker, Josie E.; Nes, W. David; Smith, Stephen N.; Kelly, Diane E.

    2015-01-01

    In this study, we investigate the amebicidal activities of the pharmaceutical triazole CYP51 inhibitors fluconazole, itraconazole, and voriconazole against Acanthamoeba castellanii and Acanthamoeba polyphaga and assess their potential as therapeutic agents against Acanthamoeba infections in humans. Amebicidal activities of the triazoles were assessed by in vitro minimum inhibition concentration (MIC) determinations using trophozoites of A. castellanii and A. polyphaga. In addition, triazole effectiveness was assessed by ligand binding studies and inhibition of CYP51 activity of purified A. castellanii CYP51 (AcCYP51) that was heterologously expressed in Escherichia coli. Itraconazole and voriconazole bound tightly to AcCYP51 (dissociation constant [Kd] of 10 and 13 nM), whereas fluconazole bound weakly (Kd of 2,137 nM). Both itraconazole and voriconazole were confirmed to be strong inhibitors of AcCYP51 activity (50% inhibitory concentrations [IC50] of 0.23 and 0.39 μM), whereas inhibition by fluconazole was weak (IC50, 30 μM). However, itraconazole was 8- to 16-fold less effective (MIC, 16 mg/liter) at inhibiting A. polyphaga and A. castellanii cell proliferation than voriconazole (MIC, 1 to 2 mg/liter), while fluconazole did not inhibit Acanthamoeba cell division (MIC, >64 mg/liter) in vitro. Voriconazole was an effective inhibitor of trophozoite proliferation for A. castellanii and A. polyphaga; therefore, it should be evaluated in trials versus itraconazole for controlling Acanthamoeba infections. PMID:26014948

  4. Cinnamaldehyde and its derivatives, a novel class of antifungal agents.

    PubMed

    Shreaz, Sheikh; Wani, Waseem A; Behbehani, Jawad M; Raja, Vaseem; Irshad, Md; Karched, Maribasappa; Ali, Intzar; Siddiqi, Weqar A; Hun, Lee Ting

    2016-07-01

    The last few decades have seen an alarming rise in fungal infections, which currently represent a global health threat. Despite extensive research towards the development of new antifungal agents, only a limited number of antifungal drugs are available in the market. The routinely used polyene agents and many azole antifungals are associated with some common side effects such as severe hepatotoxicity and nephrotoxicity. Also, antifungal resistance continues to grow and evolve and complicate patient management, despite the introduction of new antifungal agents. This suitation requires continuous attention. Cinnamaldehyde has been reported to inhibit bacteria, yeasts, and filamentous molds via the inhibition of ATPases, cell wall biosynthesis, and alteration of membrane structure and integrity. In this regard, several novel cinnamaldehyde derivatives were synthesized with the claim of potential antifungal activities. The present article describes antifungal properties of cinnamaldehyde and its derivatives against diverse classes of pathogenic fungi. This review will provide an overview of what is currently known about the primary mode of action of cinnamaldehyde. Synergistic approaches for boosting the effectiveness of cinnamaldehyde and its derivatives have been highlighted. Also, a keen analysis of the pharmacologically active systems derived from cinnamaldehyde has been discussed. Finally, efforts were made to outline the future perspectives of cinnamaldehyde-based antifungal agents. The purpose of this review is to provide an overview of current knowledge about the antifungal properties and antifungal mode of action of cinnamaldehyde and its derivatives and to identify research avenues that can facilitate implementation of cinnamaldehyde as a natural antifungal.

  5. Role of antifungal agents in the treatment of seborrheic dermatitis.

    PubMed

    Gupta, Aditya K; Nicol, Karyn; Batra, Roma

    2004-01-01

    Seborrheic dermatitis is a superficial fungal disease of the skin, occurring in areas rich in sebaceous glands. It is thought that an association exists between Malassezia yeasts and seborrheic dermatitis. This may, in part, be due to an abnormal or inflammatory immune response to these yeasts. The azoles represent the largest class of antifungals used in the treatment of this disease to date. In addition to their antifungal properties, some azoles, including bifonazole, itraconazole, and ketoconazole, have demonstrated anti-inflammatory activity, which may be beneficial in alleviating symptoms. Other topical antifungal agents, such as the allylamines (terbinafine), benzylamines (butenafine), hydroxypyridones (ciclopirox), and immunomodulators (pimecrolimus and tacrolimus), have also been effective. In addition, recent studies have revealed that tea tree oil (Melaleuca oil), honey, and cinnamic acid have antifungal activity against Malassezia species, which may be of benefit in the treatment of seborrheic dermatitis. In cases where seborrheic dermatitis is widespread, the use of an oral therapy, such as ketoconazole, itraconazole, and terbinafine, may be preferred. Essentially, antifungal therapy reduces the number of yeasts on the skin, leading to an improvement in seborrheic dermatitis. With a wide availability of preparations, including creams, shampoos, and oral formulations, antifungal agents are safe and effective in the treatment of seborrheic dermatitis.

  6. Tissue Penetration of Antifungal Agents

    PubMed Central

    Felton, Timothy; Troke, Peter F.

    2014-01-01

    SUMMARY Understanding the tissue penetration of systemically administered antifungal agents is critical for a proper appreciation of their antifungal efficacy in animals and humans. Both the time course of an antifungal drug and its absolute concentrations within tissues may differ significantly from those observed in the bloodstream. In addition, tissue concentrations must also be interpreted within the context of the pathogenesis of the various invasive fungal infections, which differ significantly. There are major technical obstacles to the estimation of concentrations of antifungal agents in various tissue subcompartments, yet these agents, even those within the same class, may exhibit markedly different tissue distributions. This review explores these issues and provides a summary of tissue concentrations of 11 currently licensed systemic antifungal agents. It also explores the therapeutic implications of their distribution at various sites of infection. PMID:24396137

  7. Azole antifungals: 35 years of invasive fungal infection management.

    PubMed

    Allen, David; Wilson, Dustin; Drew, Richard; Perfect, John

    2015-06-01

    Prior to 1981, treatment options for invasive fungal infections were limited and associated with significant toxicities. The introduction of ketoconazole marked the beginning of an era of dramatic improvements over previous therapies for non-life-threatening mycosis. After nearly a decade of use, ketoconazole was quickly replaced by the triazoles fluconazole and itraconazole due to significant improvements in pharmacokinetic profile, spectrum of activity and safety. The triazoles posaconazole and voriconazole followed, and were better known for their further extended spectrum, specifically against emerging mold infections. With the exception of fluconazole, the triazoles have been plagued with significant inter- and intrapatient pharmacokinetic variability and all possess significant drug interactions. Azoles currently in development appear to combine an in vitro spectrum of activity comparable to voriconazole and posaconazole with more predictable pharmacokinetics and fewer adverse effects.

  8. In Vitro Activity of the Antifungal Azoles Itraconazole and Posaconazole against Leishmania amazonensis

    PubMed Central

    de Macedo-Silva, Sara Teixeira; Urbina, Julio A.; de Souza, Wanderley; Rodrigues, Juliany Cola Fernandes

    2013-01-01

    Leishmaniasis, caused by protozoan parasites of the Leishmania genus, is one of the most prevalent neglected tropical diseases. It is endemic in 98 countries, causing considerable morbidity and mortality. Pentavalent antimonials are the first line of treatment for leishmaniasis except in India. In resistant cases, miltefosine, amphotericin B and pentamidine are used. These treatments are unsatisfactory due to toxicity, limited efficacy, high cost and difficult administration. Thus, there is an urgent need to develop drugs that are efficacious, safe, and more accessible to patients. Trypanosomatids, including Leishmania spp. and Trypanosoma cruzi, have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. Inhibition of ergosterol biosynthesis is increasingly recognized as a promising target for the development of new chemotherapeutic agents. The aim of this work was to investigate the antiproliferative, physiological and ultrastructural effects against Leishmania amazonensis of itraconazole (ITZ) and posaconazole (POSA), two azole antifungal agents that inhibit sterol C14α-demethylase (CYP51). Antiproliferative studies demonstrated potent activity of POSA and ITZ: for promastigotes, the IC50 values were 2.74 µM and 0.44 µM for POSA and ITZ, respectively, and for intracellular amastigotes, the corresponding values were 1.63 µM and 0.08 µM, for both stages after 72 h of treatment. Physiological studies revealed that both inhibitors induced a collapse of the mitochondrial membrane potential (ΔΨm), which was consistent with ultrastructural alterations in the mitochondrion. Intense mitochondrial swelling, disorganization and rupture of mitochondrial membranes were observed by transmission electron microscopy. In addition, accumulation of lipid bodies, appearance of autophagosome-like structures and alterations in the kinetoplast were also observed. In conclusion, our results indicate that ITZ and POSA are potent

  9. Simultaneous determination of seven azole antifungal drugs in serum by ultra-high pressure liquid chromatography and diode array detection.

    PubMed

    Mistretta, V; Dubois, N; Denooz, R; Charlier, C

    2014-01-01

    Azole antifungals are a group of fungistatic agents that can be administered orally or parenterally. The determination of the concentrations of these antifungals (miconazole, fluconazole, ketoconazole, posaconazole, voriconazole, itraconazole, and its major active metabolite, hydroxy-itraconazole) in serum can be useful to adapt the doses to pharmacological ranges because of large variability in the absorption and metabolism of the drugs, multiple drug interactions, but also potential resistance or toxicity. A method was developed and validated for the simultaneous determination of these drugs in serum utilizing ultra-high pressure liquid chromatography and diode array detection (UHPLC-DAD). After a simple and rapid liquid-liquid extraction, the pre-treated sample was analysed on an UHPLC-DAD system (Waters Corporation(®)). The chromatographic separation was carried out on an Acquity BEH C18 column (Waters Corporation) with a gradient mode of mobile phase composed of acetonitrile and aqueous ammonium bicarbonate 10·0 M pH10. The flow rate was 0·4 ml/min and the injection volume was 5 μl. The identification wavelength varied according to the drug from 210 to 260 nm. The method was validated by the total error method approach by using an analytical validation software (e•noval V3·0 Arlenda(®)). The seven azole antifungals were identified by retention time and specific UV spectra, over a 13-minute run time. All calibration curves showed good linearity (r(2)>0·99) in ranges considered clinically adequate. The assay was linear from 0·05 to 10 mg/l for voriconazole, posaconazole, itraconazole, hydroxy-itraconazole, and ketoconazole, from 0·3 to 10 mg/l for fluconazole, and from 0·1 to 10 mg/l for miconazole. The bias and imprecision values for intra- and inter-assays were lower than 10% and than 15%, respectively. In conclusion, a simple, sensitive, and selective UHPLC-DAD method was developed and validated to determine seven azole antifungal drugs in human

  10. A defect in iron uptake enhances the susceptibility of Cryptococcus neoformans to azole antifungal drugs

    PubMed Central

    Kim, Jeongmi; Cho, Yong-Joon; Do, Eunsoo; Choi, Jaehyuk; Hu, Guanggan; Cadieux, Brigitte; Chun, Jongsik; Lee, Younghoon; Kronstad, James W.; Jung, Won Hee

    2015-01-01

    The high-affinity reductive iron uptake system that includes a ferroxidase (Cfo1) and an iron permease (Cft1) is critical for the pathogenesis of Cryptococcus neoformans. In addition, a mutant lacking CFO1 or CFT1 not only has reduced iron uptake but also displays a markedly increased susceptibility to azole antifungal drugs. Altered antifungal susceptibility of the mutants was of particular interest because the iron uptake system has been proposed as an alternative target for antifungal treatment. In this study, we used transcriptome analysis to begin exploring the molecular mechanisms of altered antifungal susceptibility in a cfo1 mutant. The wild-type strain and the cfo1 mutant were cultured with or without the azole antifungal drug fluconazole and their transcriptomes were compared following sequencing with Illumina Genome Analyzer IIx (GAIIx) technology. As expected, treatment of both strains with fluconazole caused elevated expression of genes in the ergosterol biosynthetic pathway that includes the target enzyme Erg11. Additionally, genes differentially expressed in the cfo1 mutant were involved in iron uptake and homeostasis, mitochondrial functions and respiration. The cfo1 mutant also displayed phenotypes consistent with these changes including a reduced ratio of NAD+/NADH and down-regulation of Fe-S cluster synthesis. Moreover, combination treatment of the wild-type strain with fluconazole and the respiration inhibitor diphenyleneiodonium dramatically increased susceptibility to fluconazole. This result supports the hypothesis that down-regulation of genes required for respiration contributed to the altered fluconazole susceptibility of the cfo1 mutant. Overall, our data suggest that iron uptake and homeostasis play a key role in antifungal susceptibility and could be used as novel targets for combination treatment of cryptococcosis. Indeed, we found that iron chelation in combination with fluconazole treatment synergistically inhibited the growth of C

  11. The yeast Saccharomyces cerevisiae Pdr16p restricts changes in ergosterol biosynthesis caused by the presence of azole antifungals.

    PubMed

    Šimová, Zuzana; Poloncová, Katarína; Tahotná, Dana; Holič, Roman; Hapala, Ivan; Smith, Adam R; White, Theodore C; Griač, Peter

    2013-06-01

    Pdr16p belongs to the family of phosphatidylinositol transfer proteins in yeast. The absence of Pdr16p results in enhanced susceptibility to azole antifungals in Saccharomyces cerevisiae. In the major fungal human pathogen Candida albicans, CaPDR16 is a contributing factor to clinical azole resistance. The current study was aimed at better understanding the function of Pdr16p, especially in relation to azole resistance in S. cerevisiae. We show that deletion of the PDR16 gene increased susceptibility of S. cerevisiae to azole antifungals that are used in clinical medicine and agriculture. Significant differences in the inhibition of the sterol biosynthetic pathway were observed between the pdr16Δ strain and its corresponding wild-type (wt) strain when yeast cells were challenged by sub-inhibitory concentrations of the azoles miconazole or fluconazole. The increased susceptibility to azoles, and enhanced changes in sterol biosynthesis upon exposure to azoles of the pdr16Δ strain compared to wt strain, are not the results of increased intracellular concentration of azoles in the pdr16Δ cells. We also show that overexpression of PDR17 complemented the azole susceptible phenotype of the pdr16Δ strain and corrected the enhanced sterol alterations in pdr16Δ cells in the presence of azoles. Pdr17p was found previously to be an essential part of a complex required for intermembrane transport of phosphatidylserine at regions of membrane apposition. Based on these observations, we propose a hypothesis that Pdr16p assists in shuttling sterols or their intermediates between membranes or, alternatively, between sterol biosynthetic enzymes or complexes.

  12. Azole Resistance in Aspergillus fumigatus: Can We Retain the Clinical Use of Mold-Active Antifungal Azoles?

    PubMed Central

    Verweij, Paul E.; Chowdhary, Anuradha; Melchers, Willem J. G.; Meis, Jacques F.

    2016-01-01

    Azole resistance in Aspergillus fumigatus has emerged as a global health problem. Although the number of cases of azole-resistant aspergillosis is still limited, resistance mechanisms continue to emerge, thereby threatening the role of the azole class in the management of diseases caused by Aspergillus. The majority of cases of azole-resistant disease are due to resistant A. fumigatus originating from the environment. Patient management is difficult due to the absence of patient risk factors, delayed diagnosis, and limited treatment options, resulting in poor treatment outcome. International and collaborative efforts are required to understand how resistance develops in the environment to allow effective measures to be implemented aimed at retaining the use of azoles both for food production and human medicine. PMID:26486705

  13. Interaction of azole antifungal antibiotics with cytochrome P-450-dependent 14 alpha-sterol demethylase purified from Candida albicans.

    PubMed Central

    Hitchcock, C A; Dickinson, K; Brown, S B; Evans, E G; Adams, D J

    1990-01-01

    The interaction of azole antifungal antibiotics with purified Candida albicans cytochrome P-450-dependent 14 alpha-sterol demethylase (P-450DM) was measured spectrophotometrically and by inhibition of enzyme activity. Ketoconazole and ICI 153066 (a triazole derivative) formed low-spin complexes with the ferric cytochrome and induced type II difference spectra. These spectra are indicative of an interaction between the azole moiety and the sixth co-ordination position of P-450DM haem. Both azoles inhibited the binding of CO to the sodium dithionite-reduced ferrous cytochrome, and inhibited reconstituted P-450DM activity by binding to the cytochrome with a one-to-one stoichiometry. Similarly, total inhibition of enzyme activity occurred when equimolar amounts of clotrimazole, miconazole or fluconazole were added to reconstituted P-450DM. These results correlated with the inhibition of P-450DM in broken cell preparations, confirming that all five azoles are potent inhibitors of ergosterol biosynthesis in C. albicans. PMID:2180400

  14. Nectar yeasts of the Metschnikowia clade are highly susceptible to azole antifungals widely used in medicine and agriculture.

    PubMed

    Álvarez-Pérez, Sergio; de Vega, Clara; Pozo, María I; Lenaerts, Marijke; Van Assche, Ado; Herrera, Carlos M; Jacquemyn, Hans; Lievens, Bart

    2016-02-01

    The widespread use of azole antifungals in medicine and agriculture and the resulting long-persistent residues could potentially affect beneficial fungi. However, there is very little information on the tolerance of non-target environmental fungi to azoles. In this study, we assessed the susceptibility of diverse plant- and insect-associated yeasts from the Metschnikowia clade, including several ecologically important species, to widely used medical and agricultural azoles (epoxiconazole, imazalil, ketoconazole and voriconazole). A total of 120 strains from six species were tested. Minimum inhibitory concentrations (MICs) were determined by the EUCAST broth microdilution procedure after some necessary modifications were made. The majority of species tested were highly susceptible to epoxiconazole, ketoconazole and voriconazole (>95% of strains showed MICs ≤ 0.125 mg l(-1)). Most strains were also very susceptible to imazalil, although MIC values were generally higher than for the other azoles. Furthermore, certain Metschnikowia reukaufii strains displayed a 'trailing' phenotype (i.e. showed reduced but persistent growth at antifungal concentrations above the MIC), but this characteristic was dependent on test conditions. It was concluded that exposure to azoles may pose a risk for ecologically relevant yeasts from the Metschnikowia clade, and thus could potentially impinge on the tripartite interaction linking these fungi with plants and their insect pollinators.

  15. Epidemiology of invasive fungal infections in lung transplant recipients on long-term azole antifungal prophylaxis.

    PubMed

    Chong, Pearlie P; Kennedy, Cassie C; Hathcock, Matthew A; Kremers, Walter K; Razonable, Raymund R

    2015-04-01

    Lung transplant recipients (LTR) at our institution receive prolonged and mostly lifelong azole antifungal (AF) prophylaxis. The impact of this prophylactic strategy on the epidemiology and outcome of invasive fungal infections (IFI) is unknown. This was a single-center, retrospective cohort study. We reviewed the medical records of all adult LTR from January 2002 to December 2011. Overall, 16.5% (15 of 91) of patients who underwent lung transplantation during this time period developed IFI. Nineteen IFI episodes were identified (eight proven, 11 probable), 89% (17 of 19) of which developed during AF prophylaxis. LTR with idiopathic pulmonary fibrosis were more likely to develop IFI (HR: 4.29; 95% CI: 1.15-15.91; p = 0.03). A higher hazard of mortality was observed among those who developed IFI, although this was not statistically significant (hazard ratio [HR]: 1.71; 95% confidence interval [CI] [0.58-4.05]; p = 0.27). Aspergillus fumigatus was the most common cause of IFI (45%), with pulmonary parenchyma being the most common site of infection. None of our patients developed disseminated invasive aspergillosis, cryptococcal or endemic fungal infections. IFI continue to occur in LTR, and the eradication of IFI appears to be challenging even with prolonged prophylaxis. Azole resistance is uncommon despite prolonged AF exposure.

  16. Potent antimicrobial agents against azole-resistant fungi based on pyridinohydrazide and hydrazomethylpyridine structural motifs.

    PubMed

    Backes, Gregory L; Jursic, Branko S; Neumann, Donna M

    2015-07-01

    Schiff base derivatives have recently been shown to possess antimicrobial activity, and these derivatives include a limited number of salicylaldehyde hydrazones. To further explore this structure-activity relationship between salicylaldehyde hydrazones and antifungal activity, we previously synthesized and analyzed a large series of salicylaldehyde and formylpyridinetrione hydrazones for their ability to inhibit fungal growth of both azole-susceptible and azole-resistant species of Candida. While many of these analogs showed excellent growth inhibition with low mammalian cell toxicity, their activity did not extend to azole-resistant species of Candida. To further dissect the structural features necessary to inhibit azole-resistant fungal species, we synthesized a new class of modified salicylaldehyde derivatives and subsequently identified a series of modified pyridine-based hydrazones that had potent fungicidal antifungal activity against multiple Candida spp. Here we would like to present our synthetic procedures as well as the results from fungal growth inhibition assays, mammalian cell toxicity assays, time-kill assays and synergy studies of these novel pyridine-based hydrazones on both azole-susceptible and azole-resistant fungal species.

  17. Susceptibilities of Candida albicans multidrug transporter mutants to various antifungal agents and other metabolic inhibitors.

    PubMed Central

    Sanglard, D; Ischer, F; Monod, M; Bille, J

    1996-01-01

    Some Candida albicans isolates from AIDS patients with oropharyngeal candidiasis are becoming resistant to the azole antifungal agent fluconazole after prolonged treatment with this compound. Most of the C. albicans isolates resistant to fluconazole fail to accumulate this antifungal agent, and this has been considered a cause of resistance. This phenomenon was shown to be linked to an increase in the amounts of mRNA of a C. albicans ABC (ATP-binding cassette) transporter gene called CDR1 and of a gene conferring benomyl resistance (BENr), the product of which belongs to the class of major facilitator multidrug efflux transporters (D. Sanglard, K. Kuchler, F. Ischer, J. L. Pagani, M. Monod, and J. Bille, Antimicrob. Agents Chemother. 39:2378-2386, 1995). To analyze the roles of these multidrug transporters in the efflux of azole antifungal agents, we constructed C. albicans mutants with single and double deletion mutations of the corresponding genes. The mutants were tested for their susceptibilities to these antifungal agents. Our results indicated that the delta cdr1 C. albicans mutant was hypersusceptible to the azole derivatives fluconazole, itraconazole, and ketoconazole, thus showing that the ABC transporter Cdr1 can use these compounds as substrates. The delta cdr1 mutant was also hypersusceptible to other antifungal agents (terbinafine and amorolfine) and to different metabolic inhibitors (cycloheximide, brefeldin A, and fluphenazine). The same mutant was slightly more susceptible than the wild type to nocodazole, cerulenin, and crystal violet but not to amphotericin B, nikkomycin Z, flucytosine, or pradimicin. In contrast, the delta ben mutant was rendered more susceptible only to the mutagen 4-nitroquinoline-N-oxide. However, this mutation increased the susceptibilities of the cells to cycloheximide and cerulenin when the mutation was constructed in a delta cdr1 background. The assay used in the present study could be implemented with new antifungal

  18. The Synthesis and Study of Azole Carboxamide Nucleosides as Agents Active Against RNA Viruses.

    DTIC Science & Technology

    1986-09-15

    5012 62770A 62770A8,1. AH 355 11. TITLE (Include Security Classification) The Synthesis and Study of Azole Carboxamide Nucleosides as Agents Active...broad-spectrum antiviral agent has stimulated a great deal of effort toward the chemical synthesis of nucleosides of other azole heterocycles. During the...4 II. Chemistry and Discussion . . .. .. . 6 1. Synthesis of Certain 5’-Substituted Derivatives of Ribavirin and Tiazofurin . . .. . 6 2

  19. Azole antifungal inhibition of buprenorphine, methadone and oxycodone in vitro metabolism.

    PubMed

    Moody, David E; Liu, Fenyun; Fang, Wenfang B

    2015-06-01

    Opioid-related mortality rates have escalated. Drug interactions may increase blood concentrations of the opioid. We therefore used human liver microsomes (HLMs) and cDNA-expressed human cytochrome P450s (rCYPs) to study in vitro inhibition of buprenorphine metabolism to norbuprenorphine (CYP3A4 and 2C8), oxycodone metabolism to noroxycodone (CYP3A4 and 2C18) and oxymorphone (CYP2D6), and methadone metabolism to R- and S-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP; CYP3A4 and 2B6). In this study, we have examined the inhibitory effect of 12 (mostly antifungal) azoles. These compounds have a wide range of solubility; to keep organic solvent ≤1%, there was an equally wide range of highest concentration tested (e.g., itraconazole 5 µM to fluconazole 1000 µM). Inhibitors were first incubated with HLMs at three concentrations with or without preincubation of inhibitor with reducing equivalents to also screen for time-dependent inhibition (TDI). Posaconazole displayed evidence of TDI; metronidazole and albendazole had no significant effect. Azoles were next screened at the highest achievable concentration for non-CYP3A4 pathways. IC50 values (µM) were determined for most CYP3A4 pathways (ranges) and other pathways as dictated by screen results: clotrimazole (0.30 - 0.35; others >30 µM); econazole (2.2 - 4.9; 2B6 R-EDDP - 9.5, S-EDDP - 6.8; 2C8 - 6.0; 2C18 - 1.0; 2D6 - 1.2); fluconazole (7.7 - 66; 2B6 - 313, 361; 2C8 - 1240; 2C18 - 17; 2D6 - 1000); itraconazole (2.5 to >5; others >5); ketoconazole (0.032 - 0.094; 2B6 - 12, 31; 2C8 - 78; 2C18 - 0.98; 2D6 - 182); miconazole (2.3 - 7.6; 2B6 - 2.8, 2.8; 2C8 - 5.3; 2C18 - 3.1; 2D6 - 5.9); posaconazole (3.4 - 20; 2C18 - 3.8; others >30); terconazole (0.48 to >10; 2C18 - 8.1; others >10) and voriconazole (0.40 - 15; 2B6 - 2.4, 2.5; 2C8 - 170; 2C18 - 13; 2D6 >300). Modeling based on estimated Ki values and plasma concentrations from the literature suggest that the orally administered azoles, particularly

  20. Azole Antifungal Sensitivity of Sterol 14α-Demethylase (CYP51) and CYP5218 from Malassezia globosa

    PubMed Central

    Warrilow, Andrew G. S.; Price, Claire L.; Parker, Josie E.; Rolley, Nicola J.; Smyrniotis, Christopher J.; Hughes, David D.; Thoss, Vera; Nes, W. David; Kelly, Diane E.; Holman, Theodore R.; Kelly, Steven L.

    2016-01-01

    Malassezia globosa cytochromes P450 CYP51 and CYP5218 are sterol 14α-demethylase (the target of azole antifungals) and a putative fatty acid metabolism protein (and a potential azole drug target), respectively. Lanosterol, eburicol and obtusifoliol bound to CYP51 with Kd values of 32, 23 and 28 μM, respectively, catalyzing sterol 14α-demethylation with respective turnover numbers of 1.7 min−1, 5.6 min−1 and 3.4 min−1. CYP5218 bound a range of fatty acids with linoleic acid binding strongest (Kd 36 μM), although no metabolism could be detected in reconstitution assays or role in growth on lipids. Clotrimazole, fluconazole, itraconazole, ketoconazole, voriconazole and ketaminazole bound tightly to CYP51 (Kd ≤ 2 to 11 nM). In contrast, fluconazole did not bind to CYP5218, voriconazole and ketaminazole bound weakly (Kd ~107 and ~12 μM), whereas ketoconazole, clotrimazole and itraconazole bound strongest to CYP5218 (Kd ~1.6, 0.5 and 0.4 μM) indicating CYP5218 to be only a secondary target of azole antifungals. IC50 determinations confirmed M. globosa CYP51 was strongly inhibited by azole antifungals (0.15 to 0.35 μM). MIC100 studies showed itraconazole should be considered as an alternative to ketoconazole given the potency and safety profiles and the CYP51 assay system can be used in structure-activity studies in drug development. PMID:27291783

  1. Chitin synthase inhibitors as antifungal agents.

    PubMed

    Chaudhary, Preeti M; Tupe, Santosh G; Deshpande, Mukund V

    2013-02-01

    Increased risk of fungal diseases in immunocompromised patients, emerging fungal pathogens, limited repertoire of antifungal drugs and resistance development against the drugs demands for development of new and effective antifungal agents. With greater knowledge of fungal metabolism efforts are being made to inhibit specific enzymes involved in different biochemical pathways for the development of antifungal drugs. Chitin synthase is one such promising target as it is absent in plants and mammals. Nikkomycin Z, a chitin synthase inhibitor is under clinical development. Chitin synthesis in fungi, chitin synthase as a target for antifungal agent development, different chitin synthase inhibitors isolated from natural sources, randomly synthesized and modified from nikkomycin and polyoxin are discussed in this review.

  2. Antifungal agents in neonates: issues and recommendations.

    PubMed

    Almirante, Benito; Rodríguez, Dolors

    2007-01-01

    Fungal infections are responsible for considerable morbidity and mortality in the neonatal period, particularly among premature neonates. Four classes of antifungal agents are commonly used in the treatment of fungal infections in pediatric patients: polyene macrolides, fluorinated pyrimidines, triazoles, and echinocandins. Due to the paucity of pediatric data, many recommendations for the use of antifungal agents in this population are derived from the experience in adults. The purpose of this article was to review the published data on fungal infections and antifungal agents, with a focus on neonatal patients, and to provide an overview of the differences in antifungal pharmacology in neonates compared with adults. Pharmacokinetic data suggest dosing differences in children versus adult patients with some antifungals, but not all agents have been fully evaluated. The available pharmacokinetic data on the amphotericin B deoxycholate formulation in neonates exhibit considerable variability; nevertheless, the dosage regimen suggested in the neonatal population is similar to that used in adults. More pharmacokinetic information is available on the liposomal and lipid complex preparations of amphotericin B and fluconazole, and it supports their use in neonates; however, the optimal dosage and duration of therapy is difficult to establish. All amphotericin-B formulations, frequently used in combination with flucytosine, are useful for treating disseminated fungal infections and Candida meningitis in neonates. Fluconazole, with potent in vitro activity against Cryptococcus neoformans and almost all Candida spp., has been used in neonates with invasive candidiasis at dosages of 6 mg/kg/day, and for antifungal prophylaxis in high-risk neonates. There are limited data on itraconazole, voriconazole, and posaconazole use in neonates. Caspofungin, which is active against Candida spp. and Aspergillus spp., requires higher doses in children relative to adults, and dosing is

  3. Lipid-based antifungal agents: current status.

    PubMed

    Arikan, S; Rex, J H

    2001-03-01

    Immunocompromised patients are well known to be predisposed to developing invasive fungal infections. These infections are usually difficult to diagnose and more importantly, the resulting mortality rate is high. The limited number of antifungal agents available and their high rate of toxicity are the major factors complicating the issue. However, the development of lipid-based formulations of existing antifungal agents has opened a new era in antifungal therapy. The best examples are the lipid-based amphotericin B preparations, amphotericin B lipid complex (ABLC; Abelcet), amphotericin B colloidal dispersion (ABCD; Amphotec or Amphocil), and liposomal amphotericin B (AmBisome). These formulations have shown that antifungal activity is maintained while toxicity is reduced. This progress is followed by the incorporation of nystatin into liposomes. Liposomal nystatin formulation is under development and studies of it have provided encouraging data. Finally, lipid-based formulations of hamycin, miconazole, and ketoconazole have been developed but remain experimental. Advances in technology of liposomes and other lipid formulations have provided promising new tools for management of fungal infections.

  4. Impact of brief exposure to antifungal agents on the post-antifungal effect and hemolysin activity of oral Candida albicans

    PubMed Central

    ELLEPOLA, Arjuna Nishantha; KHAJAH, Rana; JAYATILAKE, Sumedha; SAMARANAYAKE, Lakshman; SHARMA, Prem; KHAN, Zia

    2015-01-01

    Post-antifungal effect (PAFE) of Candida and its production of hemolysin are determinants of candidal pathogenicity. Candida albicans is the foremost aetiological agent of oral candidosis, which can be treated with polyene, azole, and echinocandin antifungals. However, once administered, the intraoral concentrations of these drugs tend to be subtherapeutic and transient due to the diluent effect of saliva and cleansing effect of the oral musculature. Hence, intra-orally, Candida may undergo a brief exposure to antifungal drugs. Objective Therefore, the PAFE and hemolysin production of oral C. albicans isolates following brief exposure to sublethal concentrations of the foregoing antifungals were evaluated. Material and Methods A total of 50 C. albicans oral isolates obtained from smokers, diabetics, asthmatics using steroid inhalers, partial denture wearers and healthy individuals were exposed to sublethal concentrations of nystatin, amphotericin B, caspofungin, ketoconazole and fluconazole for 60 min. Thereafter, the drugs were removed and the PAFE and hemolysin production were determined by previously described turbidometric and plate assays, respectively. Results Nystatin, amphotericin B, caspofungin and ketoconazole induced mean PAFE (hours) of 2.2, 2.18, 2.2 and 0.62, respectively. Fluconazole failed to produce a PAFE. Hemolysin production of these isolates was suppressed with a percentage reduction of 12.27, 13.47, 13.33, 8.53 and 4.93 following exposure to nystatin, amphotericin B, caspofungin, ketoconazole and fluconazole, respectively. Conclusions Brief exposure to sublethal concentrations of antifungal drugs appears to exert an antifungal effect by interfering with the growth as well as hemolysin production of C. albicans. PMID:26398514

  5. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance.

    PubMed

    Ghannoum, M A; Rice, L B

    1999-10-01

    The increased use of antibacterial and antifungal agents in recent years has resulted in the development of resistance to these drugs. The significant clinical implication of resistance has led to heightened interest in the study of antimicrobial resistance from different angles. Areas addressed include mechanisms underlying this resistance, improved methods to detect resistance when it occurs, alternate options for the treatment of infections caused by resistant organisms, and strategies to prevent and control the emergence and spread of resistance. In this review, the mode of action of antifungals and their mechanisms of resistance are discussed. Additionally, an attempt is made to discuss the correlation between fungal and bacterial resistance. Antifungals can be grouped into three classes based on their site of action: azoles, which inhibit the synthesis of ergosterol (the main fungal sterol); polyenes, which interact with fungal membrane sterols physicochemically; and 5-fluorocytosine, which inhibits macromolecular synthesis. Many different types of mechanisms contribute to the development of resistance to antifungals. These mechanisms include alteration in drug target, alteration in sterol biosynthesis, reduction in the intercellular concentration of target enzyme, and overexpression of the antifungal drug target. Although the comparison between the mechanisms of resistance to antifungals and antibacterials is necessarily limited by several factors defined in the review, a correlation between the two exists. For example, modification of enzymes which serve as targets for antimicrobial action and the involvement of membrane pumps in the extrusion of drugs are well characterized in both the eukaryotic and prokaryotic cells.

  6. Effect of pH on In Vitro Susceptibility of Candida glabrata and Candida albicans to 11 Antifungal Agents and Implications for Clinical Use

    PubMed Central

    Danby, Claire S.; Boikov, Dina; Rautemaa-Richardson, Rina

    2012-01-01

    The treatment of vulvovaginal candidiasis (VVC) due to Candida glabrata is challenging, with limited therapeutic options. Unexplained disappointing clinical efficacy has been reported with systemic and topical azole antifungal agents in spite of in vitro susceptibility. Given that the vaginal pH of patients with VVC is unchanged at 4 to 4.5, we studied the effect of pH on the in vitro activity of 11 antifungal agents against 40 C. glabrata isolates and compared activity against 15 fluconazole-sensitive and 10 reduced-fluconazole-susceptibility C. albicans strains. In vitro susceptibility to flucytosine, fluconazole, voriconazole, posaconazole, itraconazole, ketoconazole, clotrimazole, miconazole, ciclopirox olamine, amphotericin B, and caspofungin was determined using the CLSI method for yeast susceptibility testing. Test media were buffered to pHs of 7, 6, 5, and 4. Under conditions of reduced pH, C. glabrata isolates remained susceptible to caspofungin and flucytosine; however, there was a dramatic increase in the MIC90 for amphotericin B and every azole drug tested. Although susceptible to other azole drugs tested at pH 7, C. albicans strains with reduced fluconazole susceptibility also demonstrated reduced susceptibility to amphotericin B and all azoles at pH 4. In contrast, fluconazole-sensitive C. albicans isolates remained susceptible at low pH to azoles, in keeping with clinical observations. In selecting agents for treatment of recurrent C. glabrata vaginitis, clinicians should recognize the limitations of in vitro susceptibility testing utilizing pH 7.0. PMID:22232293

  7. Clinical implications of globally emerging azole resistance in Aspergillus fumigatus.

    PubMed

    Meis, Jacques F; Chowdhary, Anuradha; Rhodes, Johanna L; Fisher, Matthew C; Verweij, Paul E

    2016-12-05

    Aspergillus fungi are the cause of an array of diseases affecting humans, animals and plants. The triazole antifungal agents itraconazole, voriconazole, isavuconazole and posaconazole are treatment options against diseases caused by Aspergillus However, resistance to azoles has recently emerged as a new therapeutic challenge in six continents. Although de novo azole resistance occurs occasionally in patients during azole therapy, the main burden is the aquisition of resistance through the environment. In this setting, the evolution of resistance is attributed to the widespread use of azole-based fungicides. Although ubiquitously distributed, A. fumigatus is not a phytopathogen. However, agricultural fungicides deployed against plant pathogenic moulds such as Fusarium, Mycospaerella and A. flavus also show activity against A. fumigatus in the environment and exposure of non-target fungi is inevitable. Further, similarity in molecule structure between azole fungicides and antifungal drugs results in cross-resistance of A. fumigatus to medical azoles. Clinical studies have shown that two-thirds of patients with azole-resistant infections had no previous history of azole therapy and high mortality rates between 50% and 100% are reported in azole-resistant invasive aspergillosis. The resistance phenotype is associated with key mutations in the cyp51A gene, including TR34/L98H, TR53 and TR46/Y121F/T289A resistance mechanisms. Early detection of resistance is of paramount importance and if demonstrated, either with susceptibility testing or through molecular analysis, azole monotherapy should be avoided. Liposomal amphotericin B or a combination of voriconazole and an echinocandin are recomended for azole-resistant aspergillosis.This article is part of the themed issue 'Tackling emerging fungal threats to animal health, food security and ecosystem resilience'.

  8. Nanoparticles as safe and effective delivery systems of antifungal agents: Achievements and challenges.

    PubMed

    Soliman, Ghareb M

    2017-03-19

    Invasive fungal infections are becoming a major health concern in several groups of patients leading to severe morbidity and mortality. Moreover, cutaneous fungal infections are a major cause of visits to outpatient dermatology clinics. Despite the availability of several effective agents in the antifungal drug arena, their therapeutic outcome is less than optimal due to limitations related to drug physicochemical properties and toxicity. For instance, poor aqueous solubility limits the formulation options and efficacy of several azole antifungal drugs while toxicity limits the benefits of many other drugs. Nanoparticles hold great promise to overcome these limitations due to their ability to enhance drug aqueous solubility, bioavailability and antifungal efficacy. Further, drug incorporation into nanoparticles could greatly reduce its toxicity. Despite these interesting nanoparticle features, there are only few marketed nanoparticle-based antifungal drug formulations. This review sheds light on different classes of nanoparticles used in antifungal drug delivery, such as lipid-based vesicles, polymeric micelles, solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions and dendrimers with emphasis on their advantages and limitations. Translation of these nanoformulations from the lab to the clinic could be facilitated by focusing the research on overcoming problems related to nanoparticle stability, drug loading and high cost of production and standardization.

  9. Antimycotic azoles. 6. Synthesis and antifungal properties of terconazole, a novel triazole ketal.

    PubMed

    Heeres, J; Hendrickx, R; Van Cutsem, J

    1983-04-01

    The preparation and antifungal properties of cis-1-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1, 3-dioxolan-4-yl]methoxy]phenyl]-4-(1-methylethyl)piperazine are reported. Terconazole has a high topical in vivo activity against vaginal candidosis in rats and against dermatophytosis in guinea pigs.

  10. Special Issue: Novel Antifungal Drug Discovery

    PubMed Central

    Poeta, Maurizio Del

    2016-01-01

    This Special Issue is designed to highlight the latest research and development on new antifungal compounds with mechanisms of action different from the ones of polyenes, azoles, and echinocandins. The papers presented here highlight new pathways and targets that could be exploited for the future development of new antifungal agents to be used alone or in combination with existing antifungals. A computational model for better predicting antifungal drug resistance is also presented. PMID:28058254

  11. Pickering emulsions based on cyclodextrins: A smart solution for antifungal azole derivatives topical delivery.

    PubMed

    Leclercq, Loïc; Nardello-Rataj, Véronique

    2016-01-20

    Surfactants are usually used for the preparation of emulsions. Potential drawbacks on the human body or on the environment can be observed for some of them(e.g. skin irritation, hemolysis, protein denaturation, etc.). However, it is possible to use biocompatible emulsifiers such as native cyclodextrins (CDs). The mixture of oil (paraffin oil or isopropyl myristate), water and native CDs results in the formation of Pickering emulsions. The emulsion properties were investigated by ternary phase diagrams elaboration, multiple light scattering, optical and transmission microscopies. The results prove that these Pickering emulsions were very stable against coalescence due to the dense film format the oil/water interface. The rheological behavior has shown that these emulsions remain compatible for topical applications. This kind of emulsions (biocompatibility, stability and surfactant free) has been used to obtain sustainable formulations for antifungal econazole derivatives delivery. Our results prove that these new formulations are at least as active as commercially available formulations.

  12. Quinone derivatives isolated from the endolichenic fungus Phialocephala fortinii are Mdr1 modulators that combat azole resistance in Candida albicans

    PubMed Central

    Xie, Fei; Chang, Wenqiang; Zhang, Ming; Li, Ying; Li, Wei; Shi, Hongzhuo; Zheng, Sha; Lou, Hongxiang

    2016-01-01

    One of the main azole-resistance mechanisms in Candida pathogens is the upregulation of drug efflux pumps, which compromises the efficacy of azoles and results in treatment failure. The combination of azole-antifungal agents with efflux pump inhibitors represents a promising strategy to combat fungal infection. High-throughput screening of 150 extracts obtained from endolichenic fungal cultures led to the discovery that the extract of Phialocephala fortinii exhibits potent activity for the reversal of azole resistance. From P. fortinii cultures, a total of 15 quinone derivatives, comprising 11 new derivatives and 4 known compounds, were obtained. Among these compounds, palmarumycin P3 (3) and phialocephalarin B (8) specifically modulate the expression of MDR1 to inhibit the activity of drug efflux pumps and therefore reverse azole resistance. The present study revealed Mdr1 targeting as an alternative mechanism for the discovery of new agents to fight antifungal drug resistance. PMID:27650180

  13. Synthesis, antifungal activities and qualitative structure activity relationship of carabrone hydrazone derivatives as potential antifungal agents.

    PubMed

    Wang, Hao; Ren, Shuang-Xi; He, Ze-Yu; Wang, De-Long; Yan, Xiao-Nan; Feng, Jun-Tao; Zhang, Xing

    2014-03-11

    Aimed at developing novel fungicides for relieving the ever-increasing pressure of agricultural production caused by phytopathogenic fungi, 28 new hydrazone derivatives of carabrone, a natural bioactive sesquisterpene, in three types were designed, synthesized and their antifungal activities against Botrytis cinerea and Colletotrichum lagenarium were evaluated. The result revealed that all the derivatives synthesized exhibited considerable antifungal activities in vitro and in vivo, which led to the improved activities for carabrone and its analogues and further confirmed their potential as antifungal agents.

  14. In vitro activities of new and conventional antifungal agents against clinical Scedosporium isolates.

    PubMed

    Meletiadis, Joseph; Meis, Jacques F G M; Mouton, Johan W; Rodriquez-Tudela, Juan Luis; Donnelly, J Peter; Verweij, Paul E

    2002-01-01

    The susceptibilities of 13 clinical isolates of Scedosporium apiospermum and 55 clinical isolates of S. prolificans to new and conventional drugs belonging to three different classes of antifungal agents, the azoles (miconazole, itraconazole, voriconazole, UR-9825, posaconazole), the polyenes (amphotericin B, nystatin and liposomal nystatin), and allylamines (terbinafine), were studied by use of proposed standard M38-P of NCCLS. Low growth-inhibitory antifungal activities were found in vitro for most of the drugs tested against S. prolificans isolates, with the MICs at which 90% of isolates are inhibited (MIC(90)s) being >8 microg/ml; the MIC(90)s of voriconazole and UR-9825, however, were 4 microg/ml. S. apiospermum isolates were more susceptible in vitro, with the highest activity exhibited by voriconazole (MIC(90)s, 0.5 microg/ml), followed by miconazole (MIC(90)s, 1 microg/ml), UR-9825 and posaconazole (MIC(90)s, 2 microg/ml), and itraconazole (MIC(90)s, 4 microg/ml). The MICs of terbinafine, amphotericin B, and the two formulations of nystatin (for which no statistically significant differences in antifungal activities were found for the two species) for S. apiospermum isolates were high. Cross-resistance was observed among all the azoles except posaconazole and among all the polyenes except the lipid formulation. A distribution analysis was performed with the MICs of each drug and for each species. Bimodal and skewed MIC distributions were obtained, and cutoffs indicating the borders of different MIC subpopulations of the distributions were determined on the basis of the normal plot technique. These cutoffs were in many cases reproducible between 48 and 72 h.

  15. Electrochemical behavior of the antifungal agents itraconazole, posaconazole and ketoconazole at a glassy carbon electrode.

    PubMed

    Knoth, H; Scriba, G K E; Buettner, B

    2015-06-01

    The electrochemical behavior of the azole antifungal agents itraconazole, posaconazole and ketoconazole has been investigated at a glassy carbon working electrode using cyclic voltammetry. All measurements were carried out in a supporting electrolyte solution consisting of a 1:1 (v/v) mixture of 0.1 mol L(-1) sodium phosphate buffers and acetonitrile at various substance concentrations and pH values. An amperometric cell with a three electrode system consisting of a working electrode, a palladium reference electrode and a platinum disk as the auxiliary electrode was used in all experiments. All azoles showed a similar electrochemical behavior involving two reactions. An irreversible oxidation occurred at potentials of about 0.5V. A reduction peak was detected at potentials between -0.28V and -0.14V with an associated oxidation peak, which was observed in consecutive repeated measurements at potentials between -0.03 and 0.28 V. The reduction and corresponding oxidation can be regarded as a quasi-reversible process. The proposed reaction mechanisms are an irreversible oxidation of the piperazine moiety at higher potentials as well as a reduction at lower potentials of the carbonyl group of the triazolone moiety in the case of itraconazole and posaconazole or a reduction of the methoxy group of ketoconazole.

  16. Research to Identify Effective Antifungal Agents, 1993 Annual Report.

    SciTech Connect

    Schreck, Carl

    1993-10-01

    This study is a continuation of ``Research to Identify Effective Antifungal Agents'' sponsored by Bonneville Power Administration (Schreck et al. 1990, 1991, and 1992). The objectives of the present study were to select and evaluate candidate fungicides.

  17. Research to Identify Effective Antifungal Agents, 1991 Annual Report.

    SciTech Connect

    Schreck, Carl

    1991-09-01

    This study is a continuation of ``Research to Identify Effective Antifungal Agents'' sponsored by Bonneville Power Administration (Schreck et al. 1990). The objectives of the present study was to evaluate up to 10 candidate fungicides.

  18. Chemosensitization as a Means to Augment Commercial Antifungal Agents

    PubMed Central

    Campbell, Bruce C.; Chan, Kathleen L.; Kim, Jong H.

    2012-01-01

    Antimycotic chemosensitization and its mode of action are of growing interest. Currently, use of antifungal agents in agriculture and medicine has a number of obstacles. Foremost of these is development of resistance or cross-resistance to one or more antifungal agents. The generally high expense and negative impact, or side effects, associated with antifungal agents are two further issues of concern. Collectively, these problems are exacerbated by efforts to control resistant strains, which can evolve into a treadmill of higher dosages for longer periods. This cycle in turn, inflates cost of treatment, dramatically. A further problem is stagnation in development of new and effective antifungal agents, especially for treatment of human mycoses. Efforts to overcome some of these issues have involved using combinations of available antimycotics (e.g., combination therapy for invasive mycoses). However, this approach has had inconsistent success and is often associated with a marked increase in negative side effects. Chemosensitization by natural compounds to increase effectiveness of commercial antimycotics is a somewhat new approach to dealing with the aforementioned problems. The potential for safe natural products to improve antifungal activity has been observed for over three decades. Chemosensitizing agents possess antifungal activity, but at insufficient levels to serve as antimycotics, alone. Their main function is to disrupt fungal stress response, destabilize the structural integrity of cellular and vacuolar membranes or stimulate production of reactive oxygen species, augmenting oxidative stress and apoptosis. Use of safe chemosensitizing agents has potential benefit to both agriculture and medicine. When co-applied with a commercial antifungal agent, an additive or synergistic interaction may occur, augmenting antifungal efficacy. This augmentation, in turn, lowers effective dosages, costs, negative side effects and, in some cases, countermands resistance

  19. Characterization of Tamoxifen as an Antifungal Agent Using the Yeast Schizosaccharomyces Pombe Model Organism.

    PubMed

    Zhang, Xibo; Fang, Yue; Jaiseng, Wurentuya; Hu, Lingling; Lu, Yabin; Ma, Yan; Furuyashiki, Tomoyuki

    2015-10-09

    Tamoxifen, a selective estrogen receptor modulator used for managing breast cancer, is known to have antifungal activity. However, its molecular mechanism remains unknown. Using the fission yeast Schizosaccharomyces pombe as a model organism, we have explored the mechanism involved in antifungal action of tamoxifen. Since tamoxifen was shown to inhibit the binding of calmodulin to calcineurin in fungi, we first examined involvement of these molecules and found that overexpression of a catalytic subunit of calcineurin and its constitutively active mutant as well as calmodulin increases tamoxifen sensitivity. Since terbinafine and azoles inhibit enzymes for ergosterol biosynthesis, Erg1 and Erg11, for their antifungal actions, we also examined involvement of these molecules. Overexpression of Erg1 and Erg11 reduced the sensitivity to terbinafine and azoles, respectively, but increased tamoxifen sensitivity, suggesting that ergosterol biosynthesis is differently related to the action of tamoxifen and those of terbinafine and azoles. To elucidate molecules involved in tamoxifen action, we performed a genome-wide screen for altered sensitivity to tamoxifen using a fission yeast gene deletion library, and identified various hypersensitive and resistant mutants to this drug. Notably, these mutants are rarely overlapped with those identified in similar genetic screens with currently used antifungals, suggesting a novel mode of antifungal action. Furthermore, tamoxifen augmented antifungal actions of terbinafine and azoles, suggesting synergetic actions between these drugs. Therefore, our findings suggest that calmodulin-calcineurin pathway and ergosterol biosynthesis are related to antifungal action of tamoxifen, and propose novel targets for antifungal development as well as combined therapy with tamoxifen for fungal diseases.

  20. Susceptibility variation of Malassezia pachydermatis to antifungal agents according to isolate source

    PubMed Central

    Weiler, Caroline Borges; de Jesus, Francielli Pantella Kunz; Nardi, Graziela Habib; Loreto, Érico Silva; Santurio, Janio Morais; Coutinho, Selene Dall’Acqua; Alves, Sydney Hartz

    2013-01-01

    Malassezia pachydermatis is associated with dermatomycoses and otomycosis in dogs and cats. This study compared the susceptibility of M. pachydermatis isolates from sick (G1) and healthy (G2) animals to azole and polyene antifungals using the M27-A3 protocol. Isolates from G1 animals were less sensitive to amphotericin B, nystatin, fluconazole, clotrimazole and miconazole. PMID:24159302

  1. New and emerging antifungal agents: impact on respiratory infections.

    PubMed

    Feldmesser, Marta

    2003-01-01

    Fungal pathogens are increasingly important causes of respiratory disease, yet the number of antifungal agents available for clinical use is limited. Use of amphotericin B deoxycholate is hampered by severe toxicity. Triazole agents currently available have significant drug interactions; fluconazole has a limited spectrum of activity and itraconazole was, until recently, available only in oral formulations with limited bioavailability. The development of resistance to all three agents is increasingly being recognized and some filamentous fungi are resistant to the action of all of these agents. In the past few years, new antifungal agents and new formulations of existing agents have become available.The use of liposomal amphotericin B preparations is associated with reduced, but still substantial, rates of nephrotoxicity and infusion-related reactions. An intravenous formulation of itraconazole has been introduced, and several new triazole agents have been developed, with the view of identifying agents that have enhanced potency, broader spectra of action and improved pharmacodynamic properties. One of these, voriconazole, has completed large-scale clinical trials. In addition, caspofungin, the first of a new class of agents, the echinocandins, which inhibit cell wall glucan synthesis, was approved for use in the US in 2001 as salvage therapy for invasive aspergillosis. It is hoped that the availability of these agents will have a significant impact on the morbidity and mortality of fungal respiratory infections. However, at the present time, our ability to assess their impact is limited by the problematic nature of conducting trials for antifungal therapy.

  2. Triazole antifungals: a review.

    PubMed

    Peyton, L R; Gallagher, S; Hashemzadeh, M

    2015-12-01

    Invasive fungal infections and systemic mycosis, whether from nosocomial infection or immunodeficiency, have been on an upward trend for numerous years. Despite advancements in antifungal medication, treatment in certain patients can still be difficult for reasons such as impaired organ function, limited administration routes or poor safety profiles of the available antifungal medications. The growing number of invasive fungal species becoming resistant to current antifungal medications is of appreciable concern. Triazole compounds containing one or more 1,2,4-triazole rings have been shown to contain some of the most potent antifungal properties. Itracon-azole and fluconazole were some of the first triazoles synthesized, but had limitations associated with their use. Second-generation triazoles such as voriconazole, posa-conazole, albaconazole, efinaconazole, ravuconazole and isavuconazole are all derivatives of either itraconazole or fluconazole, and designed to overcome the deficiencies of their parent drugs. The goal of this manuscript is to review antifungal agents derived from triazole.

  3. Research to Identify Effective Antifungal Agents, 1992 Annual Report.

    SciTech Connect

    Schreck, Carl

    1993-03-01

    This study is a continuation of ``Research to Identify Effective Antifungal Agents'' sponsored by Bonneville Power Administration (Schreck et al. 1990 and Schreck et al. 1991). The objectives of the present study were to select and evaluate up to 10 candidate fungicides.

  4. Enhancement of commercial antifungal agents by kojic acid

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Kojic acid (KA), a natural by-product of fungal fermentation, is a commonly used food and cosmetic additive. We show that KA increases activity of amphotericin B and strobilurin, medical and agricultural antifungal agents, respectively, possibly targeting the fungal antioxidative system. KA shows pr...

  5. Chemosensitization as a means to augment commercial antifungal agents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    There is growing list of papers on antimycotic chemosensitization and the mechanisms by which they function. Currently, antifungal agents used in agriculture and in human or veterinary medicine are confronted by a number of obstacles, the main one being continual development of resistance to one, or...

  6. In vitro and in vivo antifungal profile of a novel and long acting inhaled azole, PC945, on Aspergillus fumigatus infection.

    PubMed

    Colley, Thomas; Alanio, Alexandre; Kelly, Steven L; Sehra, Gurpreet; Kizawa, Yasuo; Warrilow, Andrew G S; Parker, Josie E; Kelly, Diane E; Kimura, Genki; Anderson-Dring, Lauren; Nakaoki, Takahiro; Sunose, Mihiro; Onions, Stuart; Crepin, Damien; Lagasse, Franz; Crittall, Matthew; Shannon, Jonathan; Cooke, Michael; Bretagne, Stéphane; King-Underwood, John; Murray, John; Ito, Kazuhiro; Strong, Pete; Rapeport, Garth

    2017-02-21

    The profile of PC945, a novel triazole antifungal, designed for administration via inhalation, has been assessed in a range of in vitro and in vivo studies. PC945 was characterized as a potent, tight-binding inhibitor of Aspergillus fumigatus sterol 14α-demethylase (CYP51A and CYP51B) activity (IC50, 0.23 μM and 0.22 μM, respectively), with characteristic type II azole binding spectra. Against 96 clinically isolated A. fumigatus strains, the MIC values of PC945 ranged from 0.032∼>8 μg/ml, whilst those of voriconazole ranged from 0.064∼4 μg/ml. Spectrophotometric analysis of the effects of PC945 against itraconazole-susceptible and -resistant A. fumigatus growth, yielded IC50 (OD) values between 0.0012∼0.034 μg/ml, whereas voriconazole (0.019∼>1 μg/ml) was less effective than PC945. PC945 was effective against a broad spectrum of pathogenic fungi (MIC ranged from 0.0078∼2 μg/ml) including Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans andRhizopus oryzae (1∼2 isolates each). In addition, when A. fumigatus hyphae or human bronchial cells were treated with PC945, and then washed, PC945 was found to be quickly absorbed into both target and non-target cells and to produce persistent antifungal effects. In temporarily neutropenic immunocompromised mice infected with A. fumigatus intranasally, 50% of the animals survived until day 7 when treated intranasally with PC945 at 0.56 μg/mouse, while posaconazole showed similar effects (44%) at 14 μg/mouse. This profile affirms that topical treatment with PC945 should provide potent antifungal activity in the lung.

  7. Azole resistance in Candida albicans.

    PubMed

    Smith, K J; Warnock, D W; Kennedy, C T; Johnson, E M; Hopwood, V; Van Cutsem, J; Vanden Bossche, H

    1986-04-01

    An isolate of Candida albicans from a patient with chronic mucocutaneous candidosis who relapsed during ketoconazole treatment was compared with a number of other azole-sensitive and azole-resistant isolates by tests in vitro and in three animal models of vaginal or disseminated infection. In-vitro tests indicated that the isolate was cross-resistant to all imidazole and triazole antifungals tested. In the animal models, treatment with miconazole, ketoconazole, itraconazole or fluconazole failed to influence the infection.

  8. Use of Antifungal Combination Therapy: Agents, Order, and Timing

    PubMed Central

    Perfect, John R.

    2010-01-01

    Given the substantial morbidity and mortality related to invasive fungal infections, treatment with a combination of antifungal agents is often considered. A growing body of literature from in vitro studies, animal models, and clinical experience provides data evaluating this approach. This review describes combination antifungal strategies for the management of cryptococcal meningitis, invasive candidiasis, invasive aspergillosis, and rare mold infections. The potential effects that sequencing and timing have on the efficacy of such approaches are discussed, with a focus on recent clinical data in this arena. PMID:20574543

  9. Recent advances in topical formulation carriers of antifungal agents.

    PubMed

    Bseiso, Eman Ahmed; Nasr, Maha; Sammour, Omaima; Abd El Gawad, Nabaweya A

    2015-01-01

    Fungal infections are amongst the most commonly encountered diseases affecting the skin. Treatment approaches include both topical and oral antifungal agents. The topical route is generally preferred due to the possible side effects of oral medication. Advances in the field of formulation may soon render outdated conventional products such as creams, ointments and gels. Several carrier systems loaded with antifungal drugs have demonstrated promising results in the treatment of skin fungal infections. Examples of these newer carriers include micelles, lipidic systems such as solid lipid nanoparticles and nanostructured lipid carriers, microemulsions and vesicular systems such as liposomes, niosomes, transfersomes, ethosomes, and penetration enhancer vesicles.

  10. The biology and chemistry of antifungal agents: a review.

    PubMed

    Kathiravan, Muthu K; Salake, Amol B; Chothe, Aparna S; Dudhe, Prashik B; Watode, Rahul P; Mukta, Maheshwar S; Gadhwe, Sandeep

    2012-10-01

    In recent years their has been an increased use of antifungal agents and has resulted in the development of resistance to drugs. Currently, use of standard antifungal therapies can be limited because of toxicity, low efficacy rates. Different types of mechanisms contribute to the development of resistance to antifungals. This has given raise to search for a new heterocycle with distinct action or multitargeted combination therapy. This review addresses the areas such as the underlying mechanisms, eight different targets such as ergosterol synthesis, chitin synthesis, ergosterol disruptors, glucan synthesis, squalene epoxidase, nucleic acid synthesis, protein synthesis, microtubules synthesis. The clinically employed drugs along with the current research work going on worldwide on different heterocycles are discussed. In recent advances various heterocycles including imidazole, benzimidazole etc., twenty three scaffolds and their lead identification are discussed.

  11. Natural products--antifungal agents derived from plants.

    PubMed

    Arif, Tasleem; Bhosale, J D; Kumar, Naresh; Mandal, T K; Bendre, R S; Lavekar, G S; Dabur, Rajesh

    2009-07-01

    A new spectrum of human fungal infections is increasing due to increased cancer, AIDS, and immunocompromised patients. The increased use of antifungal agents also resulted in the development of resistance to the present drugs. It makes necessary to discover new classes of antifungal compounds to cure fungal infections. Plants are rich source of bioactive secondary metabolites of wide variety such as tannins, terpenoids, saponins, alkaloids, flavonoids, and other compounds, reported to have in vitro antifungal properties. Since the plant kingdom provides a useful source of lead compounds of novel structure, a wide-scale investigation of species from the tropics has been considered. Therefore, the research on natural products and compounds derived from natural products has accelerated in recent years due to their importance in drug discovery. A series of molecules with antifungal activity against different strains of fungus have been found in plants, which are of great importance to humans. These molecules may be used directly or considered as a precursor for developing better molecules. This review attempts to summarize the current status of important antifungal compounds from plants.

  12. Investigation of the Sterol Composition and Azole Resistance in Field Isolates of Septoria tritici

    PubMed Central

    Joseph-Horne, T.; Hollomon, D.; Manning, N.; Kelly, S. L.

    1996-01-01

    We report here a biochemical study of resistance to azole antifungal agents in a field isolate (S-27) of a fungal phytopathogen. Isolates of Septoria tritici were compared in vitro, and their responses reflected that observed in the field, with S-27 exhibiting resistance relative to RL2. In untreated cultures, both RL2 and S-27 contained isomers of ergosterol and ergosta-5,7-dienol, although in differing concentrations. Under azole treatment, this phytopathogen exhibited a response similar to that of other pathogenic fungi, with a reduction in desmethyl sterols and an accumulation of 14(alpha)-methyl sterols, indicative of inhibition of the P450-mediating sterol 14(alpha)-demethylase. Growth arrest was attributed to the reduction of ergosterol combined with an accumulation of nonutilizable sterols. Strain S-27 exhibited an azole-resistant phenotype which was correlated with decreased cellular content of azole. PMID:16535210

  13. Antifungal relative inhibition factors: BAY l-9139, bifonazole, butoconazole, isoconazole, itraconazole (R 51211), oxiconazole, Ro 14-4767/002, sulconazole, terconazole and vibunazole (BAY n-7133) compared in vitro with nine established antifungal agents.

    PubMed

    Odds, F C; Webster, C E; Abbott, A B

    1984-08-01

    Nine new antifungal agents were tested for their activity in vitro in terms of relative inhibition factors (RIFs) against 26 isolates of Candida species, eight isolates of Aspergillus species and six isolates of dermatophyte fungi. Eight of the new compounds were azole antifungals, the ninth was a phenylmorpholine derivative. Against Candida species, all the novel compounds gave RIFs that were of a similar order to RIFs for established imidazole compounds. Two topical antifungals, butoconazole and terconazole, and two systemic antifungals, itraconazole and vibunazole, gave mean RIFs less than 60% in tests with Candida species, and therefore matched clotrimazole, ketoconazole and tioconazole in terms of RIF. However, none of the new compounds gave RIFs as low as amphotericin B against the Candida isolates. Against Aspergillus isolates, itraconazole, with a mean RIF of 25%, was even more active in vitro than amphotericin B. Vibunazole was as active as ketoconazole against Aspergillus isolates. All the new antifungals except Bay l-9139 gave very low RIFs against dermatophyte isolates, and thus matched established imidazole antifungals for inhibitory effects in vitro. In terms of RIF data, all the nine new compounds tested appear to offer reasonable potential for antifungal chemotherapy in vivo. A similar conclusion would not have been drawn from minimal inhibitory concentration data, which tended to show most of the new antifungals in a very poor light. Tests with amphotericin B, 5-fluorocytosine and ketoconazole showed that RIF can vary substantially with the pH of the test medium. For amphotericin B and ketoconazole the best activity was seen at neutral pH values; for 5-fluorocytosine the greatest inhibitory activity was found at lower pH values.

  14. Effects of antifungal agents in sap activity of Candida albicans isolates.

    PubMed

    Costa, Carolina Rodrigues; Jesuíno, Rosália Santos Amorim; de Aquino Lemos, Janine; de Fátima Lisboa Fernandes, Orionalda; Hasimoto e Souza, Lúcia Kioko; Passos, Xisto Sena; do Rosário Rodrigues Silva, Maria

    2010-02-01

    Some antifungal agents have shown to exert effects on expression of virulent factors of Candida as the production of secretory aspartyl proteinase (Sap). In this study, we sought to determine and to compare the influence of fluconazole and voriconazole in proteinase activity of this microorganism. Thirty-one isolates obtained from oral mucosa of human immunodeficiency virus positive (HIV) patients were used in this study. The minimal inhibitory concentrations (MIC) of fluconazole and voriconazole were determined using the broth microdilution method with RPMI 1640 medium and with yeast carbon base-bovine serum albumin (YCB-BSA) medium. The Sap activity following by digestion of BSA as substrate was determined for four Candida albicans strains arbitrarily chosen according to susceptibility (susceptible or resistant) to fluconazole or voriconazole. Besides, the SAP1 to SAP7 genes were screened by PCR for the same isolates that were determined by the Sap activity. In vitro susceptibility testing using the two media presented similar MIC values. Increased Sap activity was observed in resistant isolates on presence of drugs, but the Sap activity by susceptible isolates to azoles showed different behavior on the presence of drug. We detected the presence of SAP1 to SAP7 genes from all susceptible or resistant C. albicans isolates. The present study provides important data about the proteinase activity and the presence of genes of SAP family in fluconazole and voriconazole susceptible or resistant C. albicans isolates.

  15. Susceptibilities of Candida albicans mouth isolates to antifungal agents, essentials oils and mouth rinses.

    PubMed

    Carvalhinho, Sara; Costa, Ana Margarida; Coelho, Ana Cláudia; Martins, Eugénio; Sampaio, Ana

    2012-07-01

    Forty Candida albicans strains isolated from patient's mouth with fixed orthodontic appliances were analyzed to their susceptibilities to antifungal agents, mouth rinses and essential oils. Susceptibility to fluconazole, econazole, miconazole and ketoconazole, amphotericin B and nystatin was assessed by the disk diffusion (DD) method based on the Clinical and Laboratory Standards Institute M44-A protocol, and by Etest (fluconazole and amphotericin B). The susceptibilities to mouth rinses and essential oils were also determined by the DD technique. All isolates tested were susceptible (S) to amphotericin B, nystatin and fluconazole. The overall concordance between the DD and the Etest was 100% for amphotericin and fluconazole. One isolate was resistant to econazole (2.5%) and the other to ketoconazole (2.5%). Econazole and ketoconazole had the highest percentages of susceptible dose dependent (SDD), 55 and 95%, respectively. Regarding to the susceptibility isolates profile, seven phenotypes were detected, and the 3 more represented (90% of the isolates) of them were SDD to one, two or three azoles. The study of mouth rinses showed a high variability of efficacy against C. albicans. The results showed that the isolates susceptibility to essential oils differed (P < 0.05). The profile activity was: cinnamon > laurel > mint > eucalyptus > rosemary > lemon > myrrh > tangerine. The main finding was that the susceptibility to cinnamon and laurel varied among the three more representative antifungal phenotypes (P < 0.05). The susceptibility of econazole-SDD isolates to cinnamon and lemon was higher than those of the econazole-S yeasts (P < 0.05). In contrast, econazole-SDD isolates were less affected by laurel than econazole-S counterparts (P < 0.05).

  16. Phytochemicals from Cunninghamia konishii Hayata act as antifungal agents.

    PubMed

    Cheng, Sen-Sung; Chung, Min-Jay; Lin, Chun-Ya; Wang, Ya-Nan; Chang, Shang-Tzen

    2012-01-11

    The aims of the present study were to isolate and identify the antifungal compounds from the ethanolic extract of Cunninghamia konishii wood and to evaluate their antifungal activities against wood decay fungi. The results showed that the n-Hex soluble fraction of the ethanolic extract from C. konishii wood had an excellent inhibitory effect against Lenzites betulina, Trametes versicolor, Laetiporus sulphureus, and Gloeophyllum trabeum, with IC(50) values of 33, 46, 62, and 49 μg/mL, respectively. By following the bioactivity-guided fractionation procedure, four sesquiterpenes, T-cadinol, cedrol, T-muurolol, and (-)-epi-cedrol, and three diterpenes, 13-epi-manool, cis-abienol, and isoabienol, were identified from the active subfractions. Among the main constituents of the ethanolic extract from C. konishii, T-cadinol, cedrol, and T-muurolol efficiently inhibited the growth of four wood-rot fungi at the concentration of 100 μg/mL, with antifungal indices of 51.4-100.0%, 68.3-100.0%, and 39.5-100.0%, respectively. Results of this study show that the ethanolic extract of C. konishii wood may be considered as a potent source of T-cadinol, cedrol, and T-muurolol as new natural antifungal agents.

  17. Pyridine-grafted chitosan derivative as an antifungal agent.

    PubMed

    Jia, Ruixiu; Duan, Yunfei; Fang, Qiang; Wang, Xiangyang; Huang, Jianying

    2016-04-01

    Pyridine moieties were introduced into chitosan by nucleophilic substitution to afford N-(1-carboxybutyl-4-pyridinium) chitosan chloride (pyridine chitosan). The resulting chitosan derivative was well characterized, and its antifungal activity was examined, based on the inhibition of mycelial growth and spore germination. The results indicated that pyridine chitosan exhibited enhanced antifungal activity by comparison with pristine chitosan. The values of the minimum inhibitory concentration and the minimal fungicidal concentration of pyridine chitosan against Fulvia fulva were 0.13 mg/ml and 1 mg/ml, respectively, while the corresponding values against Botrytis cinerea were 0.13 mg/ml and 4 mg/ml, respectively. Severe morphological changes of pyridine chitosan-treated B. cinerea were observed, indicative that pyridine chitosan could damage and deform the structure of fungal hyphae and subsequently inhibit strain growth. Non-toxicity of pyridine chitosan was demonstrated by an acute toxicity study. These results are beneficial for assessing the potential utilization of this chitosan derivative and for exploring new functional antifungal agents with chitosan in the food industry.

  18. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology.

    PubMed

    Ashbee, H Ruth; Barnes, Rosemary A; Johnson, Elizabeth M; Richardson, Malcolm D; Gorton, Rebecca; Hope, William W

    2014-05-01

    The burden of human disease related to medically important fungal pathogens is substantial. An improved understanding of antifungal pharmacology and antifungal pharmacokinetics-pharmacodynamics has resulted in therapeutic drug monitoring (TDM) becoming a valuable adjunct to the routine administration of some antifungal agents. TDM may increase the probability of a successful outcome, prevent drug-related toxicity and potentially prevent the emergence of antifungal drug resistance. Much of the evidence that supports TDM is circumstantial. This document reviews the available literature and provides a series of recommendations for TDM of antifungal agents.

  19. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology

    PubMed Central

    Ashbee, H. Ruth; Barnes, Rosemary A.; Johnson, Elizabeth M.; Richardson, Malcolm D.; Gorton, Rebecca; Hope, William W.

    2014-01-01

    The burden of human disease related to medically important fungal pathogens is substantial. An improved understanding of antifungal pharmacology and antifungal pharmacokinetics–pharmacodynamics has resulted in therapeutic drug monitoring (TDM) becoming a valuable adjunct to the routine administration of some antifungal agents. TDM may increase the probability of a successful outcome, prevent drug-related toxicity and potentially prevent the emergence of antifungal drug resistance. Much of the evidence that supports TDM is circumstantial. This document reviews the available literature and provides a series of recommendations for TDM of antifungal agents. PMID:24379304

  20. In vitro interaction between amphotericin B and azoles in Candida albicans.

    PubMed Central

    Vazquez, J A; Arganoza, M T; Vaishampayan, J K; Akins, R A

    1996-01-01

    The use of azole prophylaxis as a measure to prevent invasive fungal infections in high-risk patients is increasing and is now the standard of care in many institutions. Previous studies disagree on whether preexposure of Candida albicans to azoles affects their subsequent susceptibility to amphotericin B (AmB). The present in vitro study indicates that azole exposure generates a subpopulation of cells that are not affected by subsequent exposure to AmB. These cells that are phenotypically resistant to AmB tolerated by most cells not exposed to azole. The percentage of cells that convert to phenotypic resistance to AmB varies with the concentration and the azole. Itraconazole is more effective than fluconazole in generating cells that are phenotypically resistant to AmB and that tolerate an otherwise lethal transient exposure to AmB. Until cells that are not exposed to fluconazole are simultaneously challenged with AmB, they are not protected to a significant extent from killing by AmB. Cells that are challenged with continuous exposure to AmB also acquire phenotypic resistance to AmB at increased frequencies by azole preexposure, but this requires that the azole be continuously present during incubation with AmB. In addition, Candida cells taken from mature colonies that are not actively growing are not susceptible to the short-term killing effects of AmB without azole preexposure. The adaptive responses of C. albicans to AmB and potentially other antifungal agents that may result from prior exposure to azoles in vitro or potentially in microenvironments in vivo that induce physiological changes may have major clinical implications. PMID:8913455

  1. Terconazole--a new antifungal agent for vulvovaginal candidiasis.

    PubMed

    Weisberg, M

    1989-01-01

    Terconazole is a new broad-spectrum antifungal agent for the treatment of vulvovaginal candidiasis. Instead of an imidazole structure, terconazole contains a triazole ring, a structure developed specifically to improve antifungal activity. Clinical studies of this antifungal agent have involved 5,500 women worldwide and a number of terconazole formulations, including 80-mg vaginal suppositories and 0.4% vaginal cream. The highlights of several large, major studies are discussed in this review article. In European studies, mycologic cure rates for terconazole regimens approached or exceeded 90%. Speed of action was rapid, and relapse rates were low. In double-blind, multicenter studies conducted in the United States, clinical cure rates for 0.4% terconazole cream ranged from 86% to 96% and microbiologic cure rates from 77% to 91% at 8 to 10 days after therapy. Most patients remained free of positive signs and symptoms and microbiologic evidence of infection at 30 to 35 days posttherapy. Symptomatic relief tended to be more rapid for patients treated with 0.4% terconazole cream than for those treated with 2.0% miconazole nitrate cream. In US studies of 80-mg terconazole suppositories, clinical cure rates 8 to 10 days after therapy were between 89% and 92%, and microbiologic cure rates were between 80% and 85%. Relapse rates were also low with this form of therapy. No statistically significant differences were found between three days of treatment with 80-mg terconazole suppositories and seven days of treatment with 100-mg miconazole nitrate suppositories. This research demonstrates that terconazole is a fast-acting, highly effective, well-tolerated therapy for vulvovaginal candidiasis.

  2. Treatment of dermatophytosis by a new antifungal agent 'apigenin'.

    PubMed

    Singh, Geeta; Kumar, Padma; Joshi, Suresh Chandra

    2014-08-01

    Dermatophytes are the most common causative agents of cutaneous mycosis and remain a major public health problem in spite of the availability of an increasing number of antifungal drugs. It was, therefore considered necessary to pursue the screening of different extracts (compounds) of selected traditional medicinal plants reportedly having antidermatophyte potential. The aim of this study was to isolate and identify specific compound from the most active extract (free flavonoid) of stem of Terminalia chebula of the selected plants to treat dermatophytosis induced on experimental mice. Mice which were experimentally induced with Trichophyton mentagrophytes were grouped in six of five animals each. To treat the lesions on infected mice, two concentrations of isolated apigenin ointment, i.e. 2.5 mg g(-1) (Api I) and 5 mg g(-1) (Api II), and terbinafine (standard) of concentration 5 mg g(-1) were used. Complete recovery from the infection was recorded on 12th day of treatment for reference drug Terbinafine and Api II (5 mg g(-1) ) concentration of ointment, whereas Api I (2.5 mg g(-1) ) ointment showed complete cure on 16th day of treatment. Fungal burden was also calculated by culturing skin scraping from infected mice's of different groups. Apigenin has shown potency as the infected animals recover completely by Api II comparable to the standard drug in 12th day. So Apigenin can be explored as an antifungal agent in the clinical treatment of dermatophytosis in future.

  3. Antifungal pharmacokinetics and pharmacodynamics.

    PubMed

    Lepak, Alexander J; Andes, David R

    2014-11-10

    Successful treatment of infectious diseases requires choice of the most suitable antimicrobial agent, comprising consideration of drug pharmacokinetics (PK), including penetration into infection site, pathogen susceptibility, optimal route of drug administration, drug dose, frequency of administration, duration of therapy, and drug toxicity. Antimicrobial pharmacokinetic/pharmacodynamic (PK/PD) studies consider these variables and have been useful in drug development, optimizing dosing regimens, determining susceptibility breakpoints, and limiting toxicity of antifungal therapy. Here the concepts of antifungal PK/PD studies are reviewed, with emphasis on methodology and application. The initial sections of this review focus on principles and methodology. Then the pharmacodynamics of each major antifungal drug class (polyenes, flucytosine, azoles, and echinocandins) is discussed. Finally, the review discusses novel areas of pharmacodynamic investigation in the study and application of combination therapy.

  4. Scaling adult doses of antifungal and antibacterial agents to children.

    PubMed

    Dawson, Thomas H

    2012-06-01

    My general pharmacokinetic scaling theory is discussed for the important matter of determining pediatric dosing for existing and new therapeutic drugs when optimal, or near-optimal, dosing for adults is known. The basis for the scaling is the requirement of a time-scaled likeness of the free-drug concentration time histories of children and adults. Broad categories of single and periodic dosing are considered. The former involves the scaling of dosage, and the latter involves both the dosage and schedule. The validity of the scaling relations is demonstrated by using measurements from previously reported clinical trials with adults and children (with ages generally 1 year or older) for the relatively new antifungal agent caspofungin and for the relatively new antibacterial agent linezolid. Standard pharmacodynamic effectiveness criteria are shown to be satisfied for the scaled dosage and schedule for children to the same extent that they are for the referenced adult. Consideration of scaling from adults to children is discussed for the case of new agents where no pediatric data are available and needed parameters are determined from in vitro measurements and preclinical animal data. A connection is also made between the allometric representation of clearance data and the dosing formulas. Limitations of the scaling results for infants because of growth and maturational matters are discussed. The general conclusion from this work is that the scaling theory does indeed have application to pediatric dosing for children, for both confirmation and refinement of present practice and guidance in pediatric treatment with new therapeutic agents.

  5. Synthesis and biological evaluation of fluconazole analogs with triazole-modified scaffold as potent antifungal agents.

    PubMed

    Hashemi, Seyedeh Mahdieh; Badali, Hamid; Irannejad, Hamid; Shokrzadeh, Mohammad; Emami, Saeed

    2015-04-01

    In order to find new azole antifungals, we have recently designed a series of triazole alcohols in which one of the 1,2,4-triazol-1-yl group in fluconazole structure has been replaced with 4-amino-5-aryl-3-mercapto-1,2,4-triazole motif. In this paper, we focused on the structural refinement of the primary lead, by removing the amino group from the structure to achieve 5-aryl-3-mercapto-1,2,4-triazole derivatives 10a-i and 11a-i. The in vitro antifungal susceptibility testing of title compounds demonstrated that most compounds had potent inhibitory activity against Candida species. Among them, 5-(2,4-dichlorophenyl)triazole analogs 10h and 11h with MIC values of <0.01 to 0.5μg/mL were 4-256 times more potent than fluconazole against Candida species.

  6. Safety and tolerability of oral antifungal agents in the treatment of fungal nail disease: a proven reality

    PubMed Central

    Elewski, Boni; Tavakkol, Amir

    2005-01-01

    Clinicians now have five oral antifungal therapeutic agents to choose from when assessing the risk–benefits associated with a particular treatment for onychomycosis (OM): griseofulvin, itraconazole, terbinafine, ketoconazole, and fluconazole. Only the first three are approved by the FDA for this indication. Griseofulvin is fungistatic and inhibits nucleic acid synthesis, arresting cell division at metaphase, and impairing fungal wall synthesis. Due to its low cure rates and high relapse, it is rarely used for treatment of onychomycosis. Itraconazole is a broad spectrum drug and is effective against dermatophytes, candida, and some nondermatophytic molds. Itraconazole works by inhibiting ergosterol synthesis via cytochrome P-450 (CYP450)-dependent demethylation step. This azole antifungal agent is metabolized in the liver by cytochrome P-450 3A4 (CYP3A4), and therefore has the potential to interact with drugs metabolized through this pathway. Terbinafine, an allylamine, is fungicidal and remains at therapeutic levels in keratinized tissues, but with a short plasma half-life of 36 hours. Terbinafine has the advantage in that it does not inhibit CYP3A4 isoenzyme during its metabolism where some 50% of all commonly prescribed drugs are metabolized. The only potentially significant drug interaction with terbinafine is with the cytochrome P-450 2D6 (CYP2D6) isoenzyme. The lack of widely reported or published clinically relevant drug interactions, and extensive experience from a large prospective, surveillance study conducted in “real world” setting with no patient exclusions, suggest that this is not a major issue. The high cure rates of terbinafine against dermatophytes, as shown in many studies since its launch in the 1990s, together with lack of clinically significant drug interactions and well established safety record, indicate the use of continuous oral terbinafine as the top choice for the treatment of onychomycosis in most patients. PMID:18360572

  7. Porosity of temporary denture soft liners containing antifungal agents

    PubMed Central

    Lima, Jozely Francisca Mello; Maciel, Janaína Gomes; Hotta, Juliana; Vizoto, Ana Carolina Pero; Honório, Heitor Marques; Urban, Vanessa Migliorini; Neppelenbroek, Karin Hermana

    2016-01-01

    ABSTRACT Incorporation of antifungals in temporary denture soft liners has been recommended for denture stomatitis treatment; however, it may affect their properties. Objective: To evaluate the porosity of a tissue conditioner (Softone) and a temporary resilient liner (Trusoft) modified by minimum inhibitory concentrations (MICs) of antifungal agents for Candida albicans biofilm. Material and Methods: The porosity was measured by water absorption, based on exclusion of the plasticizer effect. Initially, it was determined by sorption isotherms that the adequate storage solution for specimens (65×10×3.3 mm) of both materials was 50% anhydrous calcium chloride (S50). Then, the porosity factor (PF) was calculated for the study groups (n=10) formed by specimens without (control) or with drug incorporation at MICs (nystatin: Ny-0.032 g, chlorhexidine diacetate: Chx-0.064 g, or ketoconazole: Ke-0.128 g each per gram of soft liner powder) after storage in distilled water or S50 for 24 h, seven and 14 d. Data were statistically analyzed by 4-way repeated measures ANOVA and Tukey's test (α=.05). Results: Ke resulted in no significant changes in PF for both liners in water over 14 days (p>0.05). Compared with the controls, Softone and Trusoft PFs were increased at 14-day water immersion only after addition of Ny and Chx, and Chx, respectively (p<0.05). Both materials showed no significant changes in PF in up to 14 days of S50 immersion, compared with the controls (p>0.05). In all experimental conditions, Softone and Trusoft PFs were significantly lower when immersed in S50 compared with distilled water (p<0.05). Conclusions: The addition of antifungals at MICs resulted in no harmful effects for the porosity of both temporary soft liners in different periods of water immersion, except for Chx and Ny in Softone and Chx in Trusoft at 14 days. No deleterious effect was observed for the porosity of both soft liners modified by the drugs at MICs over 14 days of S50 immersion

  8. Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Several benzoic acid analogs showed antifungal activity against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis. Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids increased by addition of a methyl, methoxyl...

  9. Characterization of Antifungal Activity and Nail Penetration of ME1111, a New Antifungal Agent for Topical Treatment of Onychomycosis

    PubMed Central

    Takei-Masuda, Naomi; Kubota, Natsuki; Takahata, Sho; Ohyama, Makoto; Kaneda, Kaori; Iida, Maiko; Maebashi, Kazunori

    2015-01-01

    Fungal nail infection (onychomycosis) is a prevalent disease in many areas of the world, with a high incidence approaching 23%. Available antifungals to treat the disease suffer from a number of disadvantages, necessitating the discovery of new efficacious and safe antifungals. Here, we evaluate the in vitro antifungal activity and nail penetration ability of ME1111, a novel antifungal agent, along with comparator drugs, including ciclopirox, amorolfine, terbinafine, and itraconazole. ME1111 showed potent antifungal activity against Trichophyton rubrum and Trichophyton mentagrophytes (the major etiologic agents of onychomycosis) strains isolated in Japan and reference fungal strains with an MIC range of 0.12 to 0.5 mg/liter and an MIC50 and MIC90 of 0.5 mg/liter for both. Importantly, none of the tested isolates showed an elevated ME1111 MIC. Moreover, the antifungal activity of ME1111 was minimally affected by 5% wool keratin powder in comparison to the other antifungals tested. The ME1111 solution was able to penetrate human nails and inhibit fungal growth in a dose-dependent manner according to the TurChub assay. In contrast, 8% ciclopirox and 5% amorolfine nail lacquers showed no activity under the same conditions. ME1111 demonstrated approximately 60-fold-greater selectivity in inhibition of Trichophyton spp. than of human cell lines. Our findings demonstrate that ME1111 possesses potent antidermatophyte activity, maintains this activity in the presence of keratin, and possesses excellent human nail permeability. These results suggest that ME1111 is a promising topical medication for the treatment of onychomycosis and therefore warrants further clinical evaluation. PMID:26643333

  10. Characterization of Antifungal Activity and Nail Penetration of ME1111, a New Antifungal Agent for Topical Treatment of Onychomycosis.

    PubMed

    Tabata, Yuji; Takei-Masuda, Naomi; Kubota, Natsuki; Takahata, Sho; Ohyama, Makoto; Kaneda, Kaori; Iida, Maiko; Maebashi, Kazunori

    2016-02-01

    Fungal nail infection (onychomycosis) is a prevalent disease in many areas of the world, with a high incidence approaching 23%. Available antifungals to treat the disease suffer from a number of disadvantages, necessitating the discovery of new efficacious and safe antifungals. Here, we evaluate the in vitro antifungal activity and nail penetration ability of ME1111, a novel antifungal agent, along with comparator drugs, including ciclopirox, amorolfine, terbinafine, and itraconazole. ME1111 showed potent antifungal activity against Trichophyton rubrum and Trichophyton mentagrophytes (the major etiologic agents of onychomycosis) strains isolated in Japan and reference fungal strains with an MIC range of 0.12 to 0.5 mg/liter and an MIC50 and MIC90 of 0.5 mg/liter for both. Importantly, none of the tested isolates showed an elevated ME1111 MIC. Moreover, the antifungal activity of ME1111 was minimally affected by 5% wool keratin powder in comparison to the other antifungals tested. The ME1111 solution was able to penetrate human nails and inhibit fungal growth in a dose-dependent manner according to the TurChub assay. In contrast, 8% ciclopirox and 5% amorolfine nail lacquers showed no activity under the same conditions. ME1111 demonstrated approximately 60-fold-greater selectivity in inhibition of Trichophyton spp. than of human cell lines. Our findings demonstrate that ME1111 possesses potent antidermatophyte activity, maintains this activity in the presence of keratin, and possesses excellent human nail permeability. These results suggest that ME1111 is a promising topical medication for the treatment of onychomycosis and therefore warrants further clinical evaluation.

  11. Antifungal activities of SCY-078 (MK-3118) and standard antifungal agents against clinical non-Aspergillus mold isolates.

    PubMed

    Lamoth, Frédéric; Alexander, Barbara D

    2015-07-01

    The limited armamentarium of active and oral antifungal drugs against emerging non-Aspergillus molds is of particular concern. Current antifungal agents and the new orally available beta-1,3-d-glucan synthase inhibitor SCY-078 were tested in vitro against 135 clinical non-Aspergillus mold isolates. Akin to echinocandins, SCY-078 showed no or poor activity against Mucoromycotina and Fusarium spp. However, SCY-078 was highly active against Paecilomyces variotii and was the only compound displaying some activity against notoriously panresistant Scedosporium prolificans.

  12. Distribution of the antifungal agents sordarins across filamentous fungi.

    PubMed

    Vicente, Francisca; Basilio, Angela; Platas, Gonzalo; Collado, Javier; Bills, Gerald F; González del Val, Antonio; Martín, Jesús; Tormo, José R; Harris, Guy H; Zink, Deborah L; Justice, Michael; Kahn, Jennifer Nielsen; Peláez, Fernando

    2009-01-01

    Sordarins are a class of natural antifungal agents which act by specifically inhibiting fungal protein synthesis through their interaction with the elongation factor 2, EF2. A number of natural sordarins produced by diverse fungi of different classes have been reported in the literature. We have run an exhaustive search of sordarin-producing fungi using two different approaches consecutively, the first one being a differential sensitivity screen using a sordarin-resistant mutant yeast strain run in parallel with a wild type strain, and the second one an empiric screen against Candida albicans followed by early detection of sordarins by LC-MS analysis. Using these two strategies we have detected as many as 22 new strains producing a number of different sordarin analogues, either known (sordarin, xylarin, zofimarin) or novel (isozofimarin and 4'-O-demethyl sordarin). Sordarin and xylarin were the most frequently found compounds in the class. The producing strains were subjected to sequencing of the ITS region to determine their phylogenetic affinities. All the strains were shown to belong to the Xylariales, being distributed across three families in this order, the Xylariaceae, the Amphisphaeriaceae, and the Diatrypaceae. Despite being screened in large numbers, we did not find sordarin production in any other fungal group, including those orders where sordarin producing fungi are known to exist (i.e., Sordariales, Eurotiales, and Microascales), suggesting that the production of sordarin is a trait more frequently associated to members of the Xylariales than to any other fungal order.

  13. Acquired multi-azole resistance in Candida tropicalis during persistent urinary tract infection in a dog.

    PubMed

    Álvarez-Pérez, Sergio; García, Marta E; Cutuli, María Teresa; Fermín, María Luisa; Daza, María Ángeles; Peláez, Teresa; Blanco, José L

    2016-03-01

    Multi-azole resistance acquisition by Candida tropicalis after prolonged antifungal therapy in a dog with urinary candidiasis is reported. Pre- and post-azole treatment isolates were clonally related and had identical silent mutations in the ERG11 gene, but the latter displayed increased azole minimum inhibitory concentrations. A novel frameshift mutation in ERG3 was found in some isolates recovered after resistance development, so it appears unlikely that this mutation is responsible for multi-azole resistance.

  14. Amphiphilic Tobramycin Analogues as Antibacterial and Antifungal Agents

    PubMed Central

    Shrestha, Sanjib K.; Fosso, Marina Y.; Green, Keith D.

    2015-01-01

    In this study, we investigated the in vitro antifungal activities, cytotoxicities, and membrane-disruptive actions of amphiphilic tobramycin (TOB) analogues. The antifungal activities were established by determination of MIC values and in time-kill studies. Cytotoxicity was evaluated in mammalian cell lines. The fungal membrane-disruptive action of these analogues was studied by using the membrane-impermeable dye propidium iodide. TOB analogues bearing a linear alkyl chain at their 6″-position in a thioether linkage exhibited chain length-dependent antifungal activities. Analogues with C12 and C14 chains showed promising antifungal activities against tested fungal strains, with MIC values ranging from 1.95 to 62.5 mg/liter and 1.95 to 7.8 mg/liter, respectively. However, C4, C6, and C8 TOB analogues and TOB itself exhibited little to no antifungal activity. Fifty percent inhibitory concentrations (IC50s) for the most potent TOB analogues (C12 and C14) against A549 and Beas 2B cells were 4- to 64-fold and 32- to 64-fold higher, respectively, than their antifungal MIC values against various fungi. Unlike conventional aminoglycoside antibiotics, TOB analogues with alkyl chain lengths of C12 and C14 appear to inhibit fungi by inducing apoptosis and disrupting the fungal membrane as a novel mechanism of action. Amphiphilic TOB analogues showed broad-spectrum antifungal activities with minimal mammalian cell cytotoxicity. This study provides novel lead compounds for the development of antifungal drugs. PMID:26033722

  15. Synergistic combinations of antifungals and anti-virulence agents to fight against Candida albicans

    PubMed Central

    Cui, Jinhui; Ren, Biao; Tong, Yaojun; Dai, Huanqin; Zhang, Lixin

    2015-01-01

    Candida albicans, one of the pathogenic Candida species, causes high mortality rate in immunocompromised and high-risk surgical patients. In the last decade, only one new class of antifungal drug echinocandin was applied. The increased therapy failures, such as the one caused by multi-drug resistance, demand innovative strategies for new effective antifungal drugs. Synergistic combinations of antifungals and anti-virulence agents highlight the pragmatic strategy to reduce the development of drug resistant and potentially repurpose known antifungals, which bypass the costly and time-consuming pipeline of new drug development. Anti-virulence and synergistic combination provide new options for antifungal drug discovery by counteracting the difficulty or failure of traditional therapy for fungal infections. PMID:26048362

  16. Analysis Of Volatile Fingerprints: A Rapid Screening Method For Antifungal Agents For Efficacy Against Dermatophytes

    NASA Astrophysics Data System (ADS)

    Naraghi, Kamran; Sahgal, Natasha; Adriaans, Beverley; Barr, Hugh; Magan, Naresh

    2009-05-01

    The potential of using an electronic nose (E. nose) for rapid screening dermatophytes to antifungal agents was studied. In vitro, the 50 and 90% effective concentration (EC) values of five antifungal agents for T. rubrum and T. mentagrophytes were obtained by mycelial growth assays. Then, the qualitative volatile production patterns of the growth responses of these fungi to these values were incorporated into solid medium were analysed after 96-120 hrs incubation at 25° C using headspace analyses. Overall, results, using PCA and CA demonstrated that it is possible to differentiate between various treatments within 96-120 hrs. This study showed that potential exists for using qualitative volatile patterns as a rapid screening method for antifungal agents for microorganism. This approach could also facilitate the monitoring of antimicrobial drug activities and infection control programmes and perhaps drug resistance build up in microbial species.

  17. Isavuconazole: Pharmacology, Pharmacodynamics, and Current Clinical Experience with a New Triazole Antifungal Agent.

    PubMed

    Rybak, Jeffrey M; Marx, Kayleigh R; Nishimoto, Andrew T; Rogers, P David

    2015-11-01

    Coinciding with the continually increasing population of immunocompromised patients worldwide, the incidence of invasive fungal infections has grown over the past 4 decades. Unfortunately, infections caused by both yeasts such as Candida and molds such as Aspergillus or Mucorales remain associated with unacceptably high morbidity and mortality. In addition, the available antifungals with proven efficacy in the treatment of these infections remain severely limited. Although previously available second-generation triazole antifungals have significantly expanded the spectrum of the triazole antifungal class, these agents are laden with shortcomings in their safety profiles as well as formulation and pharmacokinetic challenges. Isavuconazole, administered as the prodrug isavuconazonium, is the latest second-generation triazole antifungal to receive U.S. Food and Drug Administration approval. Approved for the treatment of both invasive aspergillosis and invasive mucormycosis, and currently under investigation for the treatment of candidemia and invasive candidiasis, isavuconazole may have therapeutic advantages over its predecessors. With clinically relevant antifungal potency against a broad range of yeasts, dimorphic fungi, and molds, isavuconazole has a spectrum of activity reminiscent of the polyene amphotericin B. Moreover, clinical experience thus far has revealed isavuconazole to be associated with fewer toxicities than voriconazole, even when administered without therapeutic drug monitoring. These characteristics, in an agent available in both a highly bioavailable oral and a β-cyclodextrin-free intravenous formulation, will likely make isavuconazole a welcome addition to the triazole class of antifungals.

  18. Synergistic combination of violacein and azoles that leads to enhanced killing of major human pathogenic dermatophytic fungi Trichophyton rubrum.

    PubMed

    Anju, S; Kumar, Nishanth S; Krishnakumar, B; Kumar, B S Dileep

    2015-01-01

    Superficial mycoses caused by dermatophytic fungi such as Trichophyton rubrum represent the most common type of worldwide human infection affecting various keratinized tissues in our body such as the skin, hair, and nails, etc. The dermatophytic infection is a significant public health threat due to its persistent nature and high recurrence rates, and thus alternative treatments to cure this fungal infection are urgently required. The present study mainly focused on the synergistic activity of violacein with four azole drugs (ketoconazole, fluconazole, clotrimazole, and itraconazole) against T. rubrum. The synergistic antifungal activities of violacein and azoles were measured by checkerboard microdilution and time-kill assays. In our study, combinations of violacein and azoles predominantly recorded synergistic effect (FIC index < 0.5). Significant synergistic value was recorded by the combination of violacein and clotrimazole. Time-kill assay by the combination of MIC concentration of violacein and azoles recorded that the growth of the T. rubrum was significantly arrested after 4-12 h of treatment. The combination of violacein and azoles leads to the enhanced inhibition of mycelial growth and conidial germination. Moreover combination enhanced the rate of release of intracellular materials. Morphological changes by SEM analysis were also prominent with the combination. A normal human cell line [Foreskin (FS) normal fibroblast] was used to check the cytotoxicity of violacein. Interestingly violacein recorded no cytotoxicity up to 100 μg/ml. The in vitro synergistic effect of violacein and azoles against clinically relevant fungi, T. rubrum, is reported here for the first time. Finally, our findings support the potential use of the violacein as an antifungal agent especially against dermatophytic fungi T. rubrum.

  19. Synergistic combination of violacein and azoles that leads to enhanced killing of major human pathogenic dermatophytic fungi Trichophyton rubrum

    PubMed Central

    Anju, S.; Kumar, Nishanth S.; Krishnakumar, B.; Kumar, B. S. Dileep

    2015-01-01

    Superficial mycoses caused by dermatophytic fungi such as Trichophyton rubrum represent the most common type of worldwide human infection affecting various keratinized tissues in our body such as the skin, hair, and nails, etc. The dermatophytic infection is a significant public health threat due to its persistent nature and high recurrence rates, and thus alternative treatments to cure this fungal infection are urgently required. The present study mainly focused on the synergistic activity of violacein with four azole drugs (ketoconazole, fluconazole, clotrimazole, and itraconazole) against T. rubrum. The synergistic antifungal activities of violacein and azoles were measured by checkerboard microdilution and time-kill assays. In our study, combinations of violacein and azoles predominantly recorded synergistic effect (FIC index < 0.5). Significant synergistic value was recorded by the combination of violacein and clotrimazole. Time-kill assay by the combination of MIC concentration of violacein and azoles recorded that the growth of the T. rubrum was significantly arrested after 4–12 h of treatment. The combination of violacein and azoles leads to the enhanced inhibition of mycelial growth and conidial germination. Moreover combination enhanced the rate of release of intracellular materials. Morphological changes by SEM analysis were also prominent with the combination. A normal human cell line [Foreskin (FS) normal fibroblast] was used to check the cytotoxicity of violacein. Interestingly violacein recorded no cytotoxicity up to 100 μg/ml. The in vitro synergistic effect of violacein and azoles against clinically relevant fungi, T. rubrum, is reported here for the first time. Finally, our findings support the potential use of the violacein as an antifungal agent especially against dermatophytic fungi T. rubrum. PMID:26322275

  20. The Synthesis and Study of New Ribavirin Derivatives and Related Nucleoside Azole Carboxamides as Agents Active against RNA Viruses.

    DTIC Science & Technology

    1981-09-01

    UNCLASSIFIED DAMDt779-C 9046 FG65 N EhEmhEEEEmhhEI mhEEomhhEEEmhEI mmEEmmhhhEE smmhhmhohEEmhh Eu....momo L3 2 L .: 1111.25 I i4A . MICROCOPY RESOLUTION TEST...during the course of this synthetic study. Most of the compounds synthesized were tested at the U.S. Army Medical Research Institute of Infectious Diseases...nucleosides with the antiviral potency of pyrazofurin but with much less toxicity may be prepared. The problem of design- ing and synthesizing an azole

  1. Benzofurazan derivatives as antifungal agents against phytopathogenic fungi.

    PubMed

    Wang, Lili; Zhang, Ying-Ying; Wang, Lei; Liu, Feng-you; Cao, Ling-Ling; Yang, Jing; Qiao, Chunhua; Ye, Yonghao

    2014-06-10

    A series of benzofurazan derivatives were prepared and evaluated for their biological activities against four important phytopathogenic fungi, namely, Rhizoctonia solani, Sclerotinia sclerotiorum, Fusarium graminearum and Phytophthora capsici, using the mycelium growth inhibition method. The structures of these compounds were characterized by (1)H NMR, (13)C NMR, and HRMS. N-(3-chloro-4-fluorophenyl)-7-nitrobenzo[c][1,2,5]oxadiazol-4-amine (A3) displayed the maximum antifungal activity against R. solani (IC50 = 1.91 μg/mL), which is close to that of the positive control Carbendazim (IC50 = 1.42 μg/mL). For other benzofurazan derivatives with nitro group at R(4) position (A series), 9 out of 30 compounds exhibited high antifungal effect against strain R. solani, with IC50 values less than 5 μg/mL. Most of the derivatives with substituents at R(2) and R(3) positions (B series) displayed moderate growth inhibition against S. sclerotiorum (IC50 < 25 μg/mL). Also, several benzofuran derivatives with nitro group at R(4) position and another conjugated aromatic ring at the R(1) position of the phenyl ring displayed high antifungal capability against strain R. solani. Compounds with substituents at R(2) and R(3) position had moderate efficacy against strain S. sclerotiorum.

  2. Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids were increased against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis, by addition of a methyl, methoxyl or a chloro group at position 4 of the aromatic ri...

  3. QSAR of heterocyclic antifungal agents by flip regression

    NASA Astrophysics Data System (ADS)

    Deeb, Omar; Clare, Brian W.

    2008-12-01

    QSAR analysis of a set of 96 heterocyclics with antifungal activity was performed. The results reveals that a pyridine ring is more favorable than benzene as the 6-membered ring, for high activity, but thiazole is unfavorable as the 5-membered ring relative to imidazole or oxazole. Methylene is the spacer leading to the highest activity. The descriptors used are indicator variables, which account for identity of substituent, lipophilicity and volume of substituent, and total polarizability. Unlike previously reported results for this data set, our fits do not exceed the limitations set by the nature of the data itself.

  4. Pivotal Role for a Tail Subunit of the RNA Polymerase II Mediator Complex CgMed2 in Azole Tolerance and Adherence in Candida glabrata

    PubMed Central

    Borah, Sapan; Shivarathri, Raju; Srivastava, Vivek Kumar; Ferrari, Sélène; Sanglard, Dominique

    2014-01-01

    Antifungal therapy failure can be associated with increased resistance to the employed antifungal agents. Candida glabrata, the second most common cause of invasive candidiasis, is intrinsically less susceptible to the azole class of antifungals and accounts for 15% of all Candida bloodstream infections. Here, we show that C. glabrata MED2 (CgMED2), which codes for a tail subunit of the RNA polymerase II Mediator complex, is required for resistance to azole antifungal drugs in C. glabrata. An inability to transcriptionally activate genes encoding a zinc finger transcriptional factor, CgPdr1, and multidrug efflux pump, CgCdr1, primarily contributes to the elevated susceptibility of the Cgmed2Δ mutant toward azole antifungals. We also report for the first time that the Cgmed2Δ mutant exhibits sensitivity to caspofungin, a constitutively activated protein kinase C-mediated cell wall integrity pathway, and elevated adherence to epithelial cells. The increased adherence of the Cgmed2Δ mutant was attributed to the elevated expression of the EPA1 and EPA7 genes. Further, our data demonstrate that CgMED2 is required for intracellular proliferation in human macrophages and modulates survival in a murine model of disseminated candidiasis. Lastly, we show an essential requirement for CgMed2, along with the Mediator middle subunit CgNut1 and the Mediator cyclin-dependent kinase/cyclin subunit CgSrb8, for the high-level fluconazole resistance conferred by the hyperactive allele of CgPdr1. Together, our findings underscore a pivotal role for CgMed2 in basal tolerance and acquired resistance to azole antifungals. PMID:25070095

  5. Screening of Pharmacologically Active Small Molecule Compounds Identifies Antifungal Agents Against Candida Biofilms

    PubMed Central

    Watamoto, Takao; Egusa, Hiroshi; Sawase, Takashi; Yatani, Hirofumi

    2015-01-01

    Candida species have emerged as important and common opportunistic human pathogens, particularly in immunocompromised individuals. The current antifungal therapies either have toxic side effects or are insufficiently effect. The aim of this study is develop new small-molecule antifungal compounds by library screening methods using Candida albicans, and to evaluate their antifungal effects on Candida biofilms and cytotoxic effects on human cells. Wild-type C. albicans strain SC5314 was used in library screening. To identify antifungal compounds, we screened a small-molecule library of 1,280 pharmacologically active compounds (LOPAC1280TM) using an antifungal susceptibility test (AST). To investigate the antifungal effects of the hit compounds, ASTs were conducted using Candida strains in various growth modes, including biofilms. We tested the cytotoxicity of the hit compounds using human gingival fibroblast (hGF) cells to evaluate their clinical safety. Only 35 compounds were identified by screening, which inhibited the metabolic activity of C. albicans by >50%. Of these, 26 compounds had fungistatic effects and nine compounds had fungicidal effects on C. albicans. Five compounds, BAY11-7082, BAY11-7085, sanguinarine chloride hydrate, ellipticine and CV-3988, had strong fungicidal effects and could inhibit the metabolic activity of Candida biofilms. However, BAY11-7082, BAY11-7085, sanguinarine chloride hydrate and ellipticine were cytotoxic to hGF cells at low concentrations. CV-3988 showed no cytotoxicity at a fungicidal concentration. Four of the compounds identified, BAY11-7082, BAY11-7085, sanguinarine chloride hydrate and ellipticine, had toxic effects on Candida strains and hGF cells. In contrast, CV-3988 had fungicidal effects on Candida strains, but low cytotoxic effects on hGF cells. Therefore, this screening reveals agent, CV-3988 that was previously unknown to be antifungal agent, which could be a novel therapies for superficial mucosal candidiasis. PMID

  6. Notable Increasing Trend in Azole Non-susceptible Candida tropicalis Causing Invasive Candidiasis in China (August 2009 to July 2014): Molecular Epidemiology and Clinical Azole Consumption

    PubMed Central

    Fan, Xin; Xiao, Meng; Liao, Kang; Kudinha, Timothy; Wang, He; Zhang, Li; Hou, Xin; Kong, Fanrong; Xu, Ying-Chun

    2017-01-01

    Objectives: To report the notable increasing trends of C. tropicalis antifungal resistance in the past 5 years, and explore molecular epidemiology, and the relationship between clinical azoles consumption and increased resistance rate. Methods: Between August 2009 and July 2014, 507 non-duplicated C. tropicalis isolates causing invasive candidiasis were collected from 10 hospitals in China. The in vitro antifungal susceptibility of nine common agents was determined by Sensititre YeastOne™ using current available species-specific clinical breakpoint (CBPs) or epidemiological cut-off values (ECVs). A high discriminatory three-locus (ctm1, ctm3, and ctm24) microsatellite scheme was used for typing of all isolates collected. Clinical consumption of fluconazole and voriconazole was obtained and the Defined Daily Dose measurement units were assigned to the data. Results: Overall, 23.1 and 20.7% of isolates were non-susceptible to fluconazole and voriconazole, respectively. And over 5 years, the non-susceptible rate of C. tropicalis isolates to fluconazole and voriconazole continuously increased from 11.2 to 42.7% for fluconazole (P < 0.001), and from 10.4 to 39.1% for voriconazole (P < 0.001). Four genotype clusters were observed to be associated with fluconazole non-susceptible phenotype. However, the increase in azole non-susceptible rate didn't correlate with clinical azole consumption. Conclusions: The rapid emergence of azole resistant C. tropicalis strains in China is worrying, and continuous surveillance is warranted and if the trend persists, empirical therapeutic strategies for C. tropicalis invasive infections should be modified. PMID:28382028

  7. Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antifungal, antitubercular and miscellaneous anti-infective agents.

    PubMed

    Rodvold, Keith A; Yoo, Liz; George, Jomy M

    2011-11-01

    Epithelial lining fluid (ELF) is often considered to be the site of extracellular pulmonary infections. During the past 25 years, a limited number of studies have evaluated the intrapulmonary penetration of antifungal, antitubercular, antiparasitic and antiviral agents. For antifungal agents, differences in drug concentrations in ELF or bronchoalveolar lavage (BAL) fluid were observed among various formulations or routes of administration, and between agents within the same class. Aerosolized doses of deoxycholate amphotericin B, liposomal amphotericin B and amphotericin B lipid complex resulted in higher concentrations in ELF or BAL fluid than after intravenous administration. The mean concentrations in ELF following intravenous administration of both anidulafungin and micafungin ranged between 0.04 and 1.38 μg/mL, and the ELF to plasma concentration ratios (based on the area under the concentration-time curve for total drug concentrations) were between 0.18 and 0.22 during the first 3 days of therapy. Among the azole agents, intravenous administration of voriconazole resulted in the highest mean ELF concentrations (range 10.1-48.3 μg/mL) and ratio of penetration (7.1). The range of mean ELF concentrations of itraconazole and posaconazole following oral administration was 0.2-1.9 μg/mL, and the ELF to plasma concentration ratios were <1. A series of studies have evaluated the intrapulmonary penetration of first- and second-line oral antitubercular agents in healthy adult subjects and patients with AIDS. The ELF to plasma concentration ratio was >1 for isoniazid, ethambutol, pyrazinamide and ethionamide. For rifampicin (rifampin) and rifapentine, the ELF to plasma concentration ratio ranged between 0.2 and 0.32, but in alveolar macrophages the concentration of rifampicin was much higher (145-738 μg/mL compared with 3.3-7.5 μg/mL in ELF). No intrapulmonary studies have been conducted for rifabutin. Sex, AIDS status or smoking history had no significant effects

  8. In vitro activities of new triazole antifungal agents, posaconazole and voriconazole, against oral Candida isolates from patients suffering from denture stomatitis.

    PubMed

    Marcos-Arias, Cristina; Eraso, Elena; Madariaga, Lucila; Carrillo-Muñoz, Alfonso Javier; Quindós, Guillermo

    2012-01-01

    Denture stomatitis is often treated with antifungal agents but recurrences or new episodes are common, and certain episodes can be resistant. New triazoles, such as posaconazole and voriconazole, may represent useful alternatives for management. In vitro activities of amphotericin B, nystatin, miconazole, fluconazole, itraconazole, posaconazole and voriconazole against 150 oral Candida (101 C. albicans, 18 C. tropicalis, 12 C. glabrata, 11 C. guilliermondii, 4 C. parapsilosis, 2 Saccharomyces cerevisiae, 1 C. dubliniensis and 1 C. krusei) from 100 denture wearers were tested by the CLSI M27-A3 method. Resistant isolates were retested by Sensititre YeastOne and Etest. Most antifungal agents were very active. However, 4 C. glabrata (33.3%), 2 C. tropicalis (11.1%), 6 C. albicans (5.6%) and 1 C. krusei were resistant to itraconazole. Posaconazole was active against 143 yeast isolates (95.3%): 6 C. albicans (5.9%) and 1 C. tropicalis (5.6%) were resistant. Geometric mean MICs were 0.036 μg/ml for C. parapsilosis, 0.062 μg/ml for C. albicans, 0.085 μg/ml for C. tropicalis, 0.387 μg/ml for C. guilliermondii and 0.498 μg/ml for C. glabrata. Voriconazole was active against 148 isolates (98.7%) with geometric mean MICs ranging from 0.030 μg/ml for C. parapsilosis, 0.042 μg/ml for C. albicans, 0.048 μg/ml for C. tropicalis, 0.082 μg/ml for C. guilliermondii, to 0.137 μg/ml for C. glabrata. Only 2 C. albicans (2%) were resistant to voriconazole showing cross-resistance to other azoles. Posaconazole and voriconazole have excellent in vitro activities against all Candida isolates and could represent useful alternatives for recalcitrant or recurrent candidiasis.

  9. Triterpenoid glycosides from Medicago sativa as antifungal agents against Pyricularia oryzae.

    PubMed

    Abbruscato, Pamela; Tosi, Solveig; Crispino, Laura; Biazzi, Elisa; Menin, Barbara; Picco, Anna M; Pecetti, Luciano; Avato, Pinarosa; Tava, Aldo

    2014-11-19

    The antifungal properties of saponin mixtures from alfalfa (Medicago sativa L.) tops and roots, the corresponding mixtures of prosapogenins from tops, and purified saponins and sapogenins against the causal agent of rice blast Pyricularia oryzae isolates are presented. In vitro experiments highlighted a range of activities, depending upon the assayed metabolite. The antifungal effects of the most promising prosapogenin mixture from alfalfa tops were confirmed by means of in planta tests using three different Italian cultivars of rice (Oryza sativa L. ssp. japonica), known to possess high, medium, and low blast resistance. The evidenced antifungal properties of the tested metabolites allowed some considerations on their structure-activity relationship. Results indicate that prosapogenins are active compounds to prevent the fungal attack of P. oryzae on different rice cultivars. Therefore, if properly formulated, these substances could represent a promising and environmentally friendly treatment to control rice blast.

  10. In Vitro Activity of ASP2397 against Aspergillus Isolates with or without Acquired Azole Resistance Mechanisms

    PubMed Central

    Jensen, Rasmus Hare; Cuenca-Estrella, Manuel

    2015-01-01

    ASP2397 is a new compound with a novel and as-yet-unknown target different from that of licensed antifungal agents. It has activity against Aspergillus and Candida glabrata. We compared its in vitro activity against wild-type and azole-resistant A. fumigatus and A. terreus isolates with that of amphotericin B, itraconazole, posaconazole, and voriconazole. Thirty-four isolates, including 4 wild-type A. fumigatus isolates, 24 A. fumigatus isolates with alterations in CYP51A TR/L98H (5 isolates), M220 (9 isolates), G54 (9 isolates), and HapE (1 isolate), and A. terreus isolates (2 wild-type isolates and 1 isolate with an M217I CYP51A alteration), were analyzed. EUCAST E.Def 9.2 and CLSI M38-A2 MIC susceptibility testing was performed. ASP2397 MIC50 values (in milligrams per liter, with MIC ranges in parentheses) determined by EUCAST and CLSI were 0.5 (0.25 to 1) and 0.25 (0.06 to 0.25) against A. fumigatus CYP51A wild-type isolates and were similarly 0.5 (0.125 to >4) and 0.125 (0.06 to >4) against azole-resistant A. fumigatus isolates, respectively. These values were comparable to those for amphotericin B, which were 0.25 (0.125 to 0.5) and 0.25 (0.125 to 0.25) against wild-type isolates and 0.25 (0.125 to 1) and 0.25 (0.125 to 1) against isolates with azole resistance mechanisms, respectively. In contrast, MICs for the azole compounds were elevated and highest for itraconazole: >4 (1 to >4) and 4 (0.5 to >4) against isolates with azole resistance mechanisms compared to 0.125 (0.125 to 0.25) and 0.125 (0.06 to 0.25) against wild-type isolates, respectively. ASP2397 was active against A. terreus CYP51A wild-type isolates (MIC 0.5 to 1), whereas MICs of both azole and ASP2397 were elevated for the mutant isolate. ASP2397 displayed in vitro activity against A. fumigatus and A. terreus isolates which was independent of the presence or absence of azole target gene resistance mutations in A. fumigatus. The findings are promising at a time when azole-resistant A. fumigatus

  11. Gene Expression Response of Trichophyton rubrum during Coculture on Keratinocytes Exposed to Antifungal Agents

    PubMed Central

    Komoto, Tatiana Takahasi; Bitencourt, Tamires Aparecida; Silva, Gabriel; Beleboni, Rene Oliveira; Marins, Mozart; Fachin, Ana Lúcia

    2015-01-01

    Trichophyton rubrum is the most common causative agent of dermatomycoses worldwide, causing infection in the stratum corneum, nails, and hair. Despite the high prevalence of these infections, little is known about the molecular mechanisms involved in the fungal-host interaction, particularly during antifungal treatment. The aim of this work was to evaluate the gene expression of T. rubrum cocultured with keratinocytes and treated with the flavonoid trans-chalcone and the glycoalkaloid α-solanine. Both substances showed a marked antifungal activity against T. rubrum strain CBS (MIC = 1.15 and 17.8 µg/mL, resp.). Cytotoxicity assay against HaCaT cells produced IC50 values of 44.18 to trans-chalcone and 61.60 µM to α-solanine. The interaction of keratinocytes with T. rubrum conidia upregulated the expression of genes involved in the glyoxylate cycle, ergosterol synthesis, and genes encoding proteases but downregulated the ABC transporter TruMDR2 gene. However, both antifungals downregulated the ERG1 and ERG11, metalloprotease 4, serine proteinase, and TruMDR2 genes. Furthermore, the trans-chalcone downregulated the genes involved in the glyoxylate pathway, isocitrate lyase, and citrate synthase. Considering the urgent need for more efficient and safer antifungals, these results contribute to a better understanding of fungal-host interactions and to the discovery of new antifungal targets. PMID:26257814

  12. Antifungal susceptibility of Malassezia furfur, Malassezia sympodialis, and Malassezia globosa to azole drugs and amphotericin B evaluated using a broth microdilution method.

    PubMed

    Rojas, Florencia D; Sosa, María de los A; Fernández, Mariana S; Cattana, María E; Córdoba, Susana B; Giusiano, Gustavo E

    2014-08-01

    We studied the in vitro activity of fluconazole (FCZ), ketoconazole (KTZ), miconazole (MCZ), voriconazole (VCZ), itraconazole (ITZ) and amphotericin B (AMB) against the three major pathogenic Malassezia species, M. globosa, M. sympodialis, and M. furfur. Antifungal susceptibilities were determined using the broth microdilution method in accordance with Clinical and Laboratory Standards Institute reference document M27-A3. To support lipid-dependent yeast development, glucose, peptone, ox bile, malt extract, glycerol, and Tween supplements were added to Roswell Park Memorial Institute RPMI 1640 medium. The supplemented medium allowed good growth of all three species studied. The minimal inhibitory concentrations (MICs) were recorded after 72 h of incubation at 32ºC. The three species showed different susceptibility profiles for the drugs tested. Malassezia sympodialis was the most susceptible and M. furfur the least susceptible species. KTZ, ITZ, and VCZ were the most active drugs, showing low variability among isolates of the same species. FCZ, MCZ, and AMB showed high MICs and wide MIC ranges. Differences observed emphasize the need to accurately identify and evaluate antifungal susceptibility of Malassezia species. Further investigations and collaborative studies are essential for correlating in vitro results with clinical outcomes since the existing limited data do not allow definitive conclusions.

  13. In vitro antifungal activity of dihydroxyacetone against causative agents of dermatomycosis.

    PubMed

    Stopiglia, Cheila Denise Ottonelli; Vieira, Fabiane Jamono; Mondadori, Andressa Grazziotin; Oppe, Tércio Paschke; Scroferneker, Maria Lúcia

    2011-04-01

    Dihydroxyacetone (DHA), a three-carbon sugar, is the browning ingredient in commercial sunless tanning formulations. DHA preparations have been used for more than 50 years and are currently highly popular for producing temporary pigmentation resembling an ultraviolet-induced tan. In this work, the in vitro antifungal activity of dihydroxyacetone was tested against causative agents of dermatomycosis, more specifically against dermatophytes and Candida spp. The antifungal activity was determined by the broth microdilution method according to the Clinical and Laboratory Standards Institute guidelines for yeasts and filamentous fungi. The data obtained show that the fungicidal activity varied from 1.6 to 50 mg ml(-1). DHA seems to be a promising substance for the treatment of dermatomycosis because it has antifungal properties at the same concentration used in artificial suntan lotions. Therefore, it is a potential low-toxicity antifungal agent that may be used topically because of its penetration into the corneal layers of the skin.

  14. In vitro assessment of antifungal drug resistance.

    PubMed

    Holmberg, K

    1986-01-01

    Several studies have documented the variability in the susceptibility pattern of fungi to antifungal drugs, and fungi possess resistance determinants to negate the effects of antifungal agents. In vitro assessment of both resistance and susceptibility are measured by suitable concentration endpoints of the antifungal drug, the minimal inhibitory concentration (MIC). MICs serve as the main parameter to define the fungistatic action on fungi growing in culture. For the antifungals used for treatment of local mycoses, the limit between a MIC value indicating susceptibility and one indicating resistance is usually determined empirically on the basis of the correlation between MIC values, and either positive or negative response to chemotherapy. The principles of susceptibility testing of fungi are essentially the same as those for bacteria. However, testing with fungi must deal with the fact that interpretation of the results is complicated by inherent differences in fungal morphology, growth rate, and optimal culture conditions. Several factors could adversely affect the test results and must be considered in the design of susceptibility testing of fungi. It is obvious when the present data on fungal susceptibility testing are reviewed that much more work on standardization of techniques and interpretation of results is necessary. This presentation will focus on the in vitro susceptibility testing for determining primary and secondary drug resistance of griseofulvin and azole antifungal agents, and the correlation between the activities of these antifungals in vitro and in vivo.

  15. Biogenic silver nanoparticles: efficient and effective antifungal agents

    NASA Astrophysics Data System (ADS)

    Netala, Vasudeva Reddy; Kotakadi, Venkata Subbaiah; Domdi, Latha; Gaddam, Susmila Aparna; Bobbu, Pushpalatha; Venkata, Sucharitha K.; Ghosh, Sukhendu Bikash; Tartte, Vijaya

    2016-04-01

    Biogenic synthesis of silver nanoparticles (AgNPs) by exploiting various plant materials is an emerging field and considered green nanotechnology as it involves simple, cost effective and ecofriendly procedure. In the present study AgNPs were successfully synthesized using aqueous callus extract of Gymnema sylvestre. The aqueous callus extract treated with 1nM silver nitrate solution resulted in the formation of AgNPs and the surface plasmon resonance (SPR) of the formed AgNPs showed a peak at 437 nm in the UV Visible spectrum. The synthesized AgNPs were characterized using Fourier transform infrared spectroscopy (FTIR), Transmission electron microscopy (TEM), and X-ray diffraction spectroscopy (XRD). FTIR spectra showed the peaks at 3333, 2928, 2361, 1600, 1357 and 1028 cm-1 which revealed the role of different functional groups possibly involved in the synthesis and stabilization of AgNPs. TEM micrograph clearly revealed the size of the AgNPs to be in the range of 3-30 nm with spherical shape and poly-dispersed nature; it is further confirmed by Particle size analysis that the stability of AgNPs is due its high negative Zeta potential (-36.1 mV). XRD pattern revealed the crystal nature of the AgNPs by showing the braggs peaks corresponding to (111), (200), (220) and (311) planes of face-centered cubic crystal phase of silver. Selected area electron diffraction pattern showed diffraction rings and confirmed the crystalline nature of synthesized AgNPs. The synthesized AgNPs exhibited effective antifungal activity against Candida albicans, Candida nonalbicans and Candida tropicalis.

  16. The Mechanistic Targets of Antifungal Agents: An Overview

    PubMed Central

    Mazu, Tryphon K.; Bricker, Barbara A.; Flores-Rozas, Hernan; Ablordeppey, Seth Y.

    2016-01-01

    Pathogenic fungi are a major causative group for opportunistic infections (OIs). AIDS patients and other immunocompromised individuals are at risk for OIs, which if not treated appropriately, contribute to the mortality associated with their conditions. Several studies have indicated that the majority of HIV-positive patients contract fungal infections throughout the course of their disease. Similar observations have been made regarding the increased frequency of bone marrow and organ transplants, the use of antineoplastic agents, the excessive use of antibiotics, and the prolonged use of corticosteroids among others. In addition, several pathogenic fungi have developed resistance to current drugs. Together these have conspired to spur a need for developing new treatment options for OIs. To aid this effort, this article reviews the biological targets of current and emerging drugs and agents that act through these targets for the treatment of opportunistic fungal infections. PMID:26776224

  17. Comparison of the in vitro activities of newer triazoles and established antifungal agents against Trichophyton rubrum.

    PubMed

    Deng, Shuwen; Zhang, Chao; Seyedmousavi, Seyedmojtaba; Zhu, Shuang; Tan, Xin; Wen, Yiyang; Huang, Xin; Lei, Wenzhi; Zhou, Zhaojing; Fang, Wenjie; Shen, Shuaishuai; Deng, Danqi; Pan, Weihua; Liao, Wanqing

    2015-07-01

    One hundred eleven clinical Trichophyton rubrum isolates were tested against 7 antifungal agents. The geometric mean MICs of all isolates were, in increasing order: terbinafine, 0.03 mg/liter; voriconazole, 0.05 mg/liter; posaconazole, 0.11 mg/liter; isavuconazole, 0.13 mg/liter; itraconazole, 0.26 mg/liter; griseofulvin, 1.65 mg/liter; and fluconazole, 2.12 mg/liter.

  18. Azole-resistant aspergillosis.

    PubMed

    Warris, Adilia

    2015-06-01

    Azole-resistance in Aspergillus fumigatus is emerging and is becoming an increasing problem in the management of aspergillosis. Two types of development of resistance have been described; resistance acquired during azole treatment in an individual patient and through environmental exposure to fungicides. The main molecular mechanism of azole resistance in A. fumigatus is explained by mutations in the cyp51A-gene. The environmental route of resistance development is particularly worrying and may affect all patients whether azole exposed or naïve, and whether suffering from acute or chronic aspergillosis. No management guidelines to assist clinicians confronted with azole-resistant aspergillosis are available and pre-clinical and clinical evidence supporting treatment choices is scarce.

  19. Naturally occurring antifungal agents against Zygosaccharomyces bailii and their synergism.

    PubMed

    Fujita, Ken-Ichi; Kubo, Isao

    2005-06-29

    Polygodial was found to exhibit a fungicidal activity against a food spoilage yeast, Zygosaccharomyces bailii, with the minimum fungicidal concentration (MFC) of 50 microg/mL (0.17 mM). The time-kill curve study showed that polygodial was fungicidal at any growth stage. The primary action of polygodial comes from its ability to disrupt the native membrane-associated function of integral proteins as nonionic surface active agents (surfactants) followed by a decrease in plasma membrane fluidity. The fungicidal activity of polygodial was increased 128-fold in combination with a sublethal amount (equivalent of 1/2 MFC) of anethole and vice versa relative to the fungicidal activity of anethole. The fungicidal activity of sorbic acid was enhanced 512-fold in combination with 1/2 MFC of polygodial. Conversely, the fungicidal activity of polygodial was enhanced 128-fold in combination with 1/2 MFC of sorbic acid.

  20. Nonplanar property study of antifungal agent tolnaftate-spectroscopic approach

    NASA Astrophysics Data System (ADS)

    Arul Dhas, D.; Hubert Joe, I.; Roy, S. D. D.; Balachandran, S.

    2011-09-01

    Vibrational analysis of the thionocarbamate fungicide tolnaftate which is antidermatophytic, antitrichophytic and antimycotic agent, primarily inhibits the ergosterol biosynthesis in the fungus, was carried out using NIR FT-Raman and FTIR spectroscopic techniques. The equilibrium geometry, various bonding features, harmonic vibrational wavenumbers and torsional potential energy surface (PES) scan studies have been computed using density functional theory method. The detailed interpretation of the vibrational spectra has been carried out with the aid of VEDA.4 program. Vibrational spectra, natural bonding orbital (NBO) analysis and optimized molecular structure show the clear evidence for electronic interaction of thionocarbamate group with aromatic ring. Predicted electronic absorption spectrum from TD-DFT calculation has been compared with the UV-vis spectrum. The Mulliken population analysis on atomic charges and the HOMO-LUMO energy were also calculated. Vibrational analysis reveals that the simultaneous IR and Raman activation of the C-C stretching mode in the phenyl and naphthalene ring provide evidence for the charge transfer interaction between the donor and acceptor groups and is responsible for its bioactivity as a fungicide.

  1. Synthesis of Antifungal Agents from Xanthene and Thiazine Dyes and Analysis of Their Effects

    PubMed Central

    Kim, Joo Ran; Michielsen, Stephen

    2016-01-01

    Indoor fungi growth is an increasing home health problem as our homes are more tightly sealed. One thing that limits durability of the antifungal agents is the scarcity of reactive sites on many surfaces to attach these agents. In order to increase graft yield of photosensitizers to the fabrics, poly(acrylic acid-co-styrene sulfonic acid-co-vinyl benzyl rose bengal or phloxine B) were polymerized and then grafted to electrospun fabrics. In an alternative process, azure A or toluidine blue O were grafted to poly(acrylic acid), which was subsequently grafted to nanofiber-based and microfiber-based fabrics. The fabrics grafted with photosensitizers induced antifungal effects on all seven types of fungi in the order of rose bengal > phloxine B > toluidine blue O > azure A, which follows the quantum yield production of singlet oxygen for these photoactive dyes. Their inhibition rates for inactivating fungal spores decreased in the order of P. cinnamomi, T. viride, A. niger, A. fumigatus, C. globosum, P. funiculosum, and M. grisea, which is associated with lipid composition in membrane and the morphology of fungal spores. The antifungal activity was also correlated with the surface area of fabric types which grafted the photosensitizer covalently on the surface as determined by the bound color strength. PMID:28335371

  2. An Evaluation of Antifungal Agents for the Treatment of Fungal Contamination in Indoor Air Environments

    PubMed Central

    Rogawansamy, Senthaamarai; Gaskin, Sharyn; Taylor, Michael; Pisaniello, Dino

    2015-01-01

    Fungal contamination in indoor environments has been associated with adverse health effects for the inhabitants. Remediation of fungal contamination requires removal of the fungi present and modifying the indoor environment to become less favourable to growth.  This may include treatment of indoor environments with an antifungal agent to prevent future growth. However there are limited published data or advice on chemical agents suitable for indoor fungal remediation. The aim of this study was to assess the relative efficacies of five commercially available cleaning agents with published or anecdotal use for indoor fungal remediation. The five agents included two common multi-purpose industrial disinfectants (Cavicide® and Virkon®), 70% ethanol, vinegar (4.0%−4.2% acetic acid), and a plant-derived compound (tea tree (Melaleuca alternifolia) oil) tested in both a liquid and vapour form. Tea tree oil has recently generated interest for its antimicrobial efficacy in clinical settings, but has not been widely employed for fungal remediation. Each antifungal agent was assessed for fungal growth inhibition using a disc diffusion method against a representative species from two common fungal genera, (Aspergillus fumigatus and Penicillium chrysogenum), which were isolated from air samples and are commonly found in indoor air. Tea tree oil demonstrated the greatest inhibitory effect on the growth of both fungi, applied in either a liquid or vapour form. Cavicide® and Virkon® demonstrated similar, although less, growth inhibition of both genera. Vinegar (4.0%–4.2% acetic acid) was found to only inhibit the growth of P. chrysogenum, while 70% ethanol was found to have no inhibitory effect on the growth of either fungi. There was a notable inhibition in sporulation, distinct from growth inhibition after exposure to tea tree oil, Virkon®, Cavicide® and vinegar. Results demonstrate that common cleaning and antifungal agents differ in their capacity to inhibit the

  3. An evaluation of antifungal agents for the treatment of fungal contamination in indoor air environments.

    PubMed

    Rogawansamy, Senthaamarai; Gaskin, Sharyn; Taylor, Michael; Pisaniello, Dino

    2015-06-02

    Fungal contamination in indoor environments has been associated with adverse health effects for the inhabitants. Remediation of fungal contamination requires removal of the fungi present and modifying the indoor environment to become less favourable to growth.  This may include treatment of indoor environments with an antifungal agent to prevent future growth. However there are limited published data or advice on chemical agents suitable for indoor fungal remediation. The aim of this study was to assess the relative efficacies of five commercially available cleaning agents with published or anecdotal use for indoor fungal remediation. The five agents included two common multi-purpose industrial disinfectants (Cavicide® and Virkon®), 70% ethanol, vinegar (4.0%-4.2% acetic acid), and a plant-derived compound (tea tree (Melaleuca alternifolia) oil) tested in both a liquid and vapour form. Tea tree oil has recently generated interest for its antimicrobial efficacy in clinical settings, but has not been widely employed for fungal remediation. Each antifungal agent was assessed for fungal growth inhibition using a disc diffusion method against a representative species from two common fungal genera, (Aspergillus fumigatus and Penicillium chrysogenum), which were isolated from air samples and are commonly found in indoor air. Tea tree oil demonstrated the greatest inhibitory effect on the growth of both fungi, applied in either a liquid or vapour form. Cavicide® and Virkon® demonstrated similar, although less, growth inhibition of both genera. Vinegar (4.0%-4.2% acetic acid) was found to only inhibit the growth of P. chrysogenum, while 70% ethanol was found to have no inhibitory effect on the growth of either fungi. There was a notable inhibition in sporulation, distinct from growth inhibition after exposure to tea tree oil, Virkon®, Cavicide® and vinegar. Results demonstrate that common cleaning and antifungal agents differ in their capacity to inhibit the growth

  4. Antifungal activity against Candida biofilms.

    PubMed

    Iñigo, Melania; Pemán, Javier; Del Pozo, Jose L

    2012-10-01

    Candida species have two distinct lifestyles: planktonic, and surface-attached communities called biofilms. Mature C. albicans biofilms show a complex three-dimensional architecture with extensive spatial heterogeneity, and consist of a dense network of yeast, hyphae, and pseudohyphae encased within a matrix of exopolymeric material. Several key processes are likely to play vital roles at the different stages of biofilm development, such as cell-substrate and cell-cell adherence, hyphal development, and quorum sensing. Biofilm formation is a survival strategy, since biofilm yeasts are more resistant to antifungals and environmental stress. Antifungal resistance is a multifactorial process that includes multidrug efflux pumps, target proteins of the ergosterol biosynthetic pathway. Most studies agree in presenting azoles as agents with poor activity against Candida spp. biofilms. However, recent studies have demonstrated that echinocandins and amphotericin B exhibit remarkable activity against C. albicans and Candida non-albicans biofilms. The association of Candida species with biofilm formation increases the therapeutic complexity of foreign body-related yeast infections. The traditional approach to the management of these infections has been to explant the affected device. There is a strong medical but also economical motivation for the development of novel anti-fungal biofilm strategies due to the constantly increasing resistance of Candida biofilms to conventional antifungals, and the high mortality caused by related infections. A better description of the extent and role of yeast in biofilms may be critical for developing novel therapeutic strategies in the clinical setting.

  5. Activity of Isavuconazole and Other Azoles against Candida Clinical Isolates and Yeast Model Systems with Known Azole Resistance Mechanisms

    PubMed Central

    Coste, Alix T.

    2015-01-01

    Isavuconazole is a novel, broad-spectrum, antifungal azole. In order to evaluate its interactions with known azole resistance mechanisms, isavuconazole susceptibility among different yeast models and clinical isolates expressing characterized azole resistance mechanisms was tested and compared to those of fluconazole, itraconazole, posaconazole, and voriconazole. Saccharomyces cerevisiae expressing the Candida albicans and C. glabrata ATP binding cassette (ABC) transporters (CDR1, CDR2, and CgCDR1), major facilitator (MDR1), and lanosterol 14-α-sterol-demethylase (ERG11) alleles with mutations were used. In addition, pairs of C. albicans and C. glabrata strains from matched clinical isolates with known azole resistance mechanisms were investigated. The expression of ABC transporters increased all azole MICs, suggesting that all azoles tested were substrates of ABC transporters. The expression of MDR1 did not increase posaconazole, itraconazole, and isavuconazole MICs. Relative increases of azole MICs (from 4- to 32-fold) were observed for fluconazole, voriconazole, and isavuconazole when at least two mutations were present in the same ERG11 allele. Upon MIC testing of azoles with clinical C. albicans and C. glabrata isolates with known resistance mechanisms, the MIC90s of C. albicans for fluconazole, voriconazole, itraconazole, posaconazole, and isavuconazole were 128, 2, 1, 0.5, and 2 μg/ml, respectively, while in C. glabrata they were 128, 2, 4, 4, and 16 μg/ml, respectively. In conclusion, the effects of azole resistance mechanisms on isavuconazole did not differ significantly from those of other azoles. Resistance mechanisms in yeasts involving ABC transporters and ERG11 decreased the activity of isavuconazole, while MDR1 had limited effect. PMID:26482310

  6. Effect of chitosan and its derivatives as antifungal and preservative agents on postharvest green asparagus.

    PubMed

    Qiu, Miao; Wu, Chu; Ren, Gerui; Liang, Xinle; Wang, Xiangyang; Huang, Jianying

    2014-07-15

    The antifungal activity and effect of high-molecular weight chitosan (H-chitosan), low-molecular weight chitosan (L-chitosan) and carboxymethyl chitosan (C-chitosan) coatings on postharvest green asparagus were evaluated. L-chitosan and H-chitosan efficiently inhibited the radial growth of Fusarium concentricum separated from postharvest green asparagus at 4 mg/ml, which appeared to be more effective in inhibiting spore germination and germ tube elongation than that of C-chitosan. Notably, spore germination was totally inhibited by L-chitosan and H-chitosan at 0.05 mg/ml. Coated asparagus did not show any apparent sign of phytotoxicity and maintained good quality over 28 days of cold storage, according to the weight loss and general quality aspects. Present results inferred that chitosan could act as an attractive preservative agent for postharvest green asparagus owing to its antifungal activity and its ability to stimulate some defense responses during storage.

  7. Chromatographic and electrophoretic techniques used in the analysis of triazole antifungal agents-a review.

    PubMed

    Ekiert, R J; Krzek, J; Talik, P

    2010-09-15

    Systematic review of literature coupled with integrative research of published data for triazole antifungal agents was done. The investigated literature covered chromatographic and electrophoretic methods developed in the last 10 years (2000-2009). The aim of this review was to compare different methodologies, assess preferences in the selection of analytical methods and to find still existing analytical problems. Last decade is characterized by dynamic development of instrumental methods, that results in advance and diversity of applied analytical procedures. The main focus was given to high-performance liquid chromatography (HPLC), the technique of choice in the analysis of most of pharmaceuticals. The review includes literature on 8 triazole antifungal drugs: fluconazole, itraconazole and terconazole from the first generation and posaconazole, voriconazole, ravuconazole, isavuconazole and albaconazole classified in second generation. Investigations of pharmaceutical formulations and biological samples were considered.

  8. Addressing current medical needs in invasive fungal infection prevention and treatment with new antifungal agents, strategies and formulations.

    PubMed

    Pitman, Stuart K; Drew, Richard H; Perfect, John R

    2011-09-01

    Introduction: Morbidity and mortality associated with invasive fungal infections (IFIs) remains unacceptably high. Such diseases represent a substantial burden to the healthcare system. New options are needed to address antifungal resistance in existing and emerging pathogens and improve treatment outcomes while minimizing drug-related toxicities and interactions. Awareness of new and potential future options is of great value for those healthcare professionals who care for patients with IFIs. Areas covered: A search of PubMed, infectious diseases conference abstracts and reference lists from relevant publications was conducted and relevant information abstracted. This review describes the limitations of existing systemic antifungal therapies (e.g., resistance, drug-drug interactions, drug-related toxicities) and summarizes data regarding several emerging antifungal compounds including (but not limited to) new triazoles (e.g. isavuconazole, ravuconazole), echinocandins (e.g., aminocandin) and nikkomycin Z. Agents in clinical trials such as (but not limited to) new triazoles (e.g., isavuconazole, ravuconazole), echinocandins (e.g., aminocandin) and nikkomycin are included. New formulations of existing drugs including reformulations of miconazole, posaconazole and amphotericin B are also reviewed. Finally, new or novel administration strategies for existing drugs such as combination antifungal therapy, antifungal dose escalation, adjunctive use of iron chelators and preemptive therapy are discussed. Expert opinion: All present antifungal agents have some deficiencies in antifungal spectra, toxicity, pharmacokinetics and/or drug-drug interactions, making them less than ideal for some fungal infections. Therefore, there remains an urgent need to find safe, effective, rapidly fungicidal, broad-spectrum antifungal agents with excellent pharmacodynamics to effectively eliminate the fungus from the body with short antifungal courses.

  9. Plant-derived antifungal agent poacic acid targets β-1,3-glucan

    DOE PAGES

    Piotrowski, Jeff S.; Okada, Hiroki; Lu, Fachuang; ...

    2015-03-09

    A rise in resistance to current antifungals necessitates strategies to identify alternative sources of effective fungicides. We report the discovery of poacic acid, a potent antifungal compound found in lignocellulosic hydrolysates of grasses. Chemical genomics using Saccharomyces cerevisiae showed that loss of cell wall synthesis and maintenance genes conferred increased sensitivity to poacic acid. Morphological analysis revealed that cells treated with poacic acid behaved similarly to cells treated with other cell wall-targeting drugs and mutants with deletions in genes involved in processes related to cell wall biogenesis. Poacic acid causes rapid cell lysis and is synergistic with caspofungin and fluconazole.more » The cellular target was identified; poacic acid localized to the cell wall and inhibited β-1,3-glucan synthesis in vivo and in vitro, apparently by directly binding β-1,3-glucan. Through its activity on the glucan layer, poacic acid inhibits growth of the fungi Sclerotinia sclerotiorum and Alternaria solani as well as the oomycete Phytophthora sojae. A single application of poacic acid to leaves infected with the broad-range fungal pathogen S. sclerotiorum substantially reduced lesion development. In conclusion, the discovery of poacic acid as a natural antifungal agent targeting β-1,3-glucan highlights the potential side use of products generated in the processing of renewable biomass toward biofuels as a source of valuable bioactive compounds and further clarifies the nature and mechanism of fermentation inhibitors found in lignocellulosic hydrolysates.« less

  10. Plant-derived antifungal agent poacic acid targets β-1,3-glucan

    SciTech Connect

    Piotrowski, Jeff S.; Okada, Hiroki; Lu, Fachuang; Li, Sheena C.; Hinchman, Li; Ranjan, Ashish; Smith, Damon L.; Higbee, Alan J.; Ulbrich, Arne; Coon, Joshua J.; Deshpande, Raamesh; Bukhman, Yury V.; McIlwain, Sean; Ong, Irene M.; Myers, Chad L.; Boone, Charles; Landick, Robert; Ralph, John; Kabbage, Mehdi; Ohya, Yoshikazu

    2015-03-09

    A rise in resistance to current antifungals necessitates strategies to identify alternative sources of effective fungicides. We report the discovery of poacic acid, a potent antifungal compound found in lignocellulosic hydrolysates of grasses. Chemical genomics using Saccharomyces cerevisiae showed that loss of cell wall synthesis and maintenance genes conferred increased sensitivity to poacic acid. Morphological analysis revealed that cells treated with poacic acid behaved similarly to cells treated with other cell wall-targeting drugs and mutants with deletions in genes involved in processes related to cell wall biogenesis. Poacic acid causes rapid cell lysis and is synergistic with caspofungin and fluconazole. The cellular target was identified; poacic acid localized to the cell wall and inhibited β-1,3-glucan synthesis in vivo and in vitro, apparently by directly binding β-1,3-glucan. Through its activity on the glucan layer, poacic acid inhibits growth of the fungi Sclerotinia sclerotiorum and Alternaria solani as well as the oomycete Phytophthora sojae. A single application of poacic acid to leaves infected with the broad-range fungal pathogen S. sclerotiorum substantially reduced lesion development. In conclusion, the discovery of poacic acid as a natural antifungal agent targeting β-1,3-glucan highlights the potential side use of products generated in the processing of renewable biomass toward biofuels as a source of valuable bioactive compounds and further clarifies the nature and mechanism of fermentation inhibitors found in lignocellulosic hydrolysates.

  11. Genomic identification of potential targets unique to Candida albicans for the discovery of antifungal agents.

    PubMed

    Tripathi, Himanshu; Luqman, Suaib; Meena, Abha; Khan, Feroz

    2014-01-01

    Despite of modern antifungal therapy, the mortality rates of invasive infection with human fungal pathogen Candida albicans are up to 40%. Studies suggest that drug resistance in the three most common species of human fungal pathogens viz., C. albicans, Aspergillus fumigatus (causing mortality rate up to 90%) and Cryptococcus neoformans (causing mortality rate up to 70%) is due to mutations in the target enzymes or high expression of drug transporter genes. Drug resistance in human fungal pathogens has led to an imperative need for the identification of new targets unique to fungal pathogens. In the present study, we have used a comparative genomics approach to find out potential target proteins unique to C. albicans, an opportunistic fungus responsible for severe infection in immune-compromised human. Interestingly, many target proteins of existing antifungal agents showed orthologs in human cells. To identify unique proteins, we have compared proteome of C. albicans [SC5314] i.e., 14,633 total proteins retrieved from the RefSeq database of NCBI, USA with proteome of human and non-pathogenic yeast Saccharomyces cerevisiae. Results showed that 4,568 proteins were identified unique to C. albicans as compared to those of human and later when these unique proteins were compared with S. cerevisiae proteome, finally 2,161 proteins were identified as unique proteins and after removing repeats total 1,618 unique proteins (42 functionally known, 1,566 hypothetical and 10 unknown) were selected as potential antifungal drug targets unique to C. albicans.

  12. Lactobacillus amylovorus DSM 19280 as a novel food-grade antifungal agent for bakery products.

    PubMed

    Ryan, Liam A M; Zannini, Emanuele; Dal Bello, Fabio; Pawlowska, Agata; Koehler, Peter; Arendt, Elke K

    2011-04-29

    Mould spoilage is the main cause of substantial economic loss in bakery industry and might also cause public health problems due to the production of mycotoxins. The reduction of mould growth in bakery products is thus of crucial importance and there is great interest to develop safe and efficient strategies for this purpose. In this study Lactobacillus amylovorus DSM19280 has been shown to produce a wide spectrum of antifungal compounds active against common bread spoilage fungi. Among the indicator moulds, Aspergillus fumigatus and Fusarium culmorum were the most sensitive organisms. Several antifungal compounds were found to be present in synthetic medium inoculated with L. amylovorus DSM19280 strain, some of them being reported here for the first time. Wheat doughs fermented with L. amylovorus DSM19280 had good rheological properties and the breads thereof were of high quality as shown by rheofermentometer and texture analyser measurements. The results were compared with those obtained with a control non-antifungal L. amylovorus DSM20531(T) strain, a non-acidified and a chemically acidified dough. The quality of sourdough and bread fermented with L. amylovorus DSM 19280 was comparable to that obtained by using L. amylovorus DSM20531 (T). Additionally, breads were evaluated for the ability to retard the growth of Fusarium culmorum FST 4.05, Aspergillus niger FST4.21, Penicillium expansum FST 4.22, Penicillium roqueforti FST 4.11 and fungal flora from the bakery environment. The biological preservation of bread with L. amylovorus DSM 19280 was also compared to the most commonly used antifungal agent Calcium propionate. Breads containing sourdough fermented with L. amylovorus DSM 19280 were more effective in extending the shelf life of bread than the calcium propionate.

  13. In Search of the Holy Grail of Antifungal Therapy

    PubMed Central

    Chapman, Stanley W.; Sullivan, Donna C.; Cleary, John D.

    2008-01-01

    The ideal antifungal agent remains an elusive goal for treatment of life-threatening systemic fungal infections. Such an agent would have broad antifungal activity, low rates of resistance, flexible routes of administration, few associated adverse events, and limited drug-drug interactions. Only three of the seven classes of antifungal agents currently available are suitable for treatment of systemic infection: the polyenes, the azoles, and the echinocandins. None match all the characteristics of an ideal agent, the Holy Grail of antifungal therapy. Academia and industry need to collaborate in the search for new lead antifungal compounds using traditional screening methods as well as the new pharmacogenomics methods. Enhancing efficacy and reducing toxicity of the currently available therapeutic agents is also another important avenue of study. As an example, the Mycosis Research Center at the University of Mississippi Medical Center has identified pyogenic polyenes in commercial preparations of amphotericin B deoxycholate which correlate with infusion related toxicities. A highly purified formulation of amphotericin B appears promising, with a better therapeutic index compared to its parent compound as evidenced by results of in vitro and in vivo studies reviewed in this presentation. PMID:18596853

  14. [Could antifungal lock be useful in the management of candidiasis linked with catheters?].

    PubMed

    Cateau, Estelle; Rodier, Marie-Hélène; Imbert, Christine

    2012-01-01

    Fungal biofilms associated with inserted medical devices such as catheters, represent a major risk factor for candidemia. In addition, these biofilm yeasts show a decreased susceptibility to antifungal agents. Recently, a new therapeutic approach has emerged, the "lock therapy", based on the use of high concentrations of antimicrobials, instilled into the lumen of the catheter and left in place for 8 to 12 h. In vitro or in vivo studies have evaluated the interest of antifungal locks using amphotericin B, an azole or echinocandins. The promising results will permit us to discuss the relevance of this technique.

  15. Antifungal drug resistance among Candida species: mechanisms and clinical impact.

    PubMed

    Sanguinetti, Maurizio; Posteraro, Brunella; Lass-Flörl, Cornelia

    2015-06-01

    The epidemiology of Candida infections has changed in recent years. Although Candida albicans is still the main cause of invasive candidiasis in most clinical settings, a substantial proportion of patients is now infected with non-albicans Candida species. The various Candida species vary in their susceptibility to the most commonly used antifungal agents, and the intrinsic resistance to antifungal therapy seen in some species, along with the development of acquired resistance during treatment in others, is becoming a major problem in the management of Candida infection. A better understanding of the mechanisms and clinical impact of antifungal drug resistance is essential for the efficient treatment of patients with Candida infection and for improving treatment outcomes. Herein, we report resistance to the azoles and echinocandins among Candida species.

  16. In Vitro Antifungal Activities against Moulds Isolated from Dermatological Specimens

    PubMed Central

    Mohd Nizam, Tzar; Binting, Rabiatul Adawiyah AG.; Mohd Saari, Shafika; Kumar, Thivyananthini Vijaya; Muhammad, Marianayati; Satim, Hartini; Yusoff, Hamidah; Santhanam, Jacinta

    2016-01-01

    Background This study aimed to determine the minimum inhibitory concentrations (MICs) of various antifungal agents against moulds isolated from dermatological specimens. Methods We identified 29 moulds from dermatological specimens between October 2012 and March 2013 by conventional methods. We performed antifungal susceptibility testing on six antifungal agents, amphotericin B, clotrimazole, itraconazole, ketoconazole, miconazole and terbinafine, according to the Clinical and Laboratory Standards Institute guidelines contained in the M38-A2 document. Results Most antifungal agents were active against the dermatophytes, except for terbinafine against Trichophyton rubrum (geometric mean MIC, MICGM 3.17 μg/mL). The dematiaceous moulds were relatively susceptible to amphotericin B and azoles (MICGM 0.17–0.34 μg/mL), but not to terbinafine (MICGM 3.62 μg/mL). Septate hyaline moulds showed variable results between the relatively more susceptible Aspergillus spp. (MICGM 0.25–4 μg/mL) and the more resistant Fusarium spp. (MICGM 5.66–32 μg/mL). The zygomycetes were susceptible to amphotericin B (MICGM 0.5 μg/mL) and clotrimazole (MICGM 0.08 μg/mL), but not to other azoles (MICGM 2.52–4 μg/mL). Conclusion Amphotericin B and clotrimazole were the most effective antifungal agents against all moulds excepting Fusarium spp., while terbinafine was useful against dermatophytes (except T. rubrum) and Aspergillus spp. However, a larger study is required to draw more solid conclusions. PMID:27418867

  17. Improved method for azole antifungal susceptibility testing.

    PubMed Central

    Gordon, M A; Lapa, E W; Passero, P G

    1988-01-01

    A reproducible method is described for the determination of the MICs of ketoconazole, miconazole, fluconazole, and itraconazole with sharp endpoints when employed with either yeasts or molds. A semisolid medium is used with controlled pH and standardized inoculum. The time of reading results is a critical factor in the conduct of this test. The medium is simple to prepare and has a relatively long refrigerator shelf life in a user-ready state, requiring only the addition of a freshly prepared inoculum after restoration to room temperature. Images PMID:2846651

  18. Antifungal drug discovery, six new molecules patented after 10 years of feast: why do we need new patented drugs apart from new strategies?

    PubMed

    Krcmery, Vladimir; Kalavsky, Erich

    2007-11-01

    After 10 years absence (between 1990-1999) of new antifungal agents and intensive research being introduced into clinical practice, 3 new azoles (Voriconazole - Pfizer, Posaconazole - Schering-Plough, Ravuconazole - Bristol-Myers Squibb) and 3 new echinocandins (Caspofungin - MSD, Anidulafungin - Astellas-Pfizer, Micafungin - Fujisawa) were patented. The question raises if we really need 6 new antifungal agents in such a short time? Perhaps, they are not here because we need them all, but because of at least fifteen years effort of many groups of investigators who successfully discovered, proved and introduced these agents to the drug market. Voriconazole (2000), Posaconazole (2005), Ravuconazole (2007) from the group of azoles; and Caspofungin (2002), Anidulafungin (2004) and Micafungin (2006) from the group of echinocandins, with unique mode(s) of action (cell wall synthesis inhibition) different from polyens, azoles, antimetabolites and new monoclonal antifungal antibody (Mycograb), were approved and introduced to the clinical practice. This paper contains some useful information regarding the recent patents on antifungal drug discovery, their current position in the strategy of treatment of invasive fungal infections is briefly reviewed.

  19. COMPARISON OF THE ACTIVITIES OF FOUR ANTIFUNGAL AGENTS IN AN IN VITRO MODEL OF DERMATOPHYTE NAIL INFECTION

    PubMed Central

    Nowrozi, Hossein; Nazeri, Golrokh; Adimi, Parvaneh; Bashashati, Mohsen; Emami, Masood

    2008-01-01

    Background: Onychomycosis is a difficult condition to treat and cure rates are disappointing. Moreover fungicidal action of antifungal agents in NCCLS assays and their rapid accumulation in nails in vivo are not compatible with the duration of treatment. Aims: This study aimed to find the effectiveness of 4 different antifungal agents in an in vitro model with some similarities to in vivo conditions. Materials and Methods: Strains of Trichophyton rubrum I-III, Trichophyton mentagrophytes (usual form), Trichophyton mentagrophytes 73, Epidermophyton Flucosom, Microsporum Canis, and Trichophyton Schoenleini which were isolated from the nails of patients, were hired. Inocula suspensions were prepared from 7 to 14 day-old cultures of dermatophytes. Antifungal agents including fluconazole, ketoconazole, terbinafine, and griseofulvin were obtained as standard powders. For each antifungal agent, initial MIC was calculated by registering the optical density for 10 two-fold serially diluted forms which was incubated with diluted fungal suspensions with RPMI 1640. Human nail powder inoculated with different strains and incubated in RPMI 1640 and different concentrations of antifungal drugs for 4 weeks. Final MIC at different steps of 1, 2, 3 and 4 weeks were investigated. Results: The final MIC that resulted from the incubation of dermatophytes with nail powder was much more than the initial which was concluded from conventional MIC assay. Terbinafine had the lowest rate of initial and final MICs. Conclusion: The model described here may present more similar conditions to clinical fungal infections; therefore the results such as MIC may be more helpful for hiring the most effective antifungal agent. PMID:19882010

  20. Toxicity of Topical Antifungal Agents to Stratified Human Cultivated Corneal Epithelial Sheets

    PubMed Central

    Kimakura, Mikiko; Yokoo, Seiichi; Nakagawa, Suguru; Yamagami, Satoru; Amano, Shiro

    2014-01-01

    Abstract Purpose: Prolonged use of topical antifungal agents may compromise corneal epithelial integrity. Here, we used an in vitro model of human stratified corneal epithelium to compare the ocular toxicity profiles of 4 different antifungal eye drops. Methods: Human corneal epithelial cell sheets were cultured in a serum-free medium containing 0.1% micafungin, 1% voriconazole, 5% pimaricin, 0.1% amphotericin B, or controls (saline or 5% glucose). Cell viability and barrier function were measured by WST-1 assay and carboxyfluorescein permeability assay, respectively. Cell migration was measured on a wound healing assay. Results: WST-1 assay and carboxyfluorescein permeability assay revealed that amphotericin B was the most toxic drug, followed by pimaricin, micafungin, and voriconazole. Cell migration on a wound healing assay was decreased in the following order, amphotericin B, pimaricin, micafungin, and voriconazole. Conclusions: Topical micafungin and voriconazole appeared to be the least toxic to the corneal epithelium. Drug prescription should consider not only fungal species and susceptibility but also ocular toxicity and stage of treatment. PMID:25280055

  1. [Ajoene the main active compound of garlic (Allium sativum): a new antifungal agent].

    PubMed

    Ledezma, Eliades; Apitz-Castro, Rafael

    2006-06-01

    The curative properties of garlic in medicine have been known for a long time. But, it was only in the last three decades when garlic properties were seriously investigated confirming its potential as therapeutic agent. Allicin, ajoene, thiosulfinates and a wide range of other organosulphurate compounds, are known to be the constituents linked to the garlic properties. Regarding the biochemical properties of these compounds, ajoene [(E,Z)-4,5,9 Trithiadodeca 1,6,11 Triene 9-oxide] is stable in water, and it can be obtained by chemical synthesis. There is evidence that some of the garlic constituents exert a wide variety of effects on different biological systems. However, ajoene is the garlic compound related to more biological activities, as showed in in vitro and in vivo systems. Those studies found that ajoene has antithrombotic, anti-tumoral,antifungal, and antiparasitic effects. This study deals with a recently described antifungal property of ajoene, and its potential use in clinical trails to treat several fungal infections.

  2. Chitosan silver nanocomposite (CAgNC) as an antifungal agent against Candida albicans.

    PubMed

    Kulatunga, Dcm; Dananjaya, Shs; Godahewa, G I; Lee, Jehee; De Zoysa, Mahanama

    2017-02-01

    Due to limited numbers of antifungal drugs and emergence of drug resistance have directed to develop nonconventional therapeutic agents against fungal pathogen Candida albicans. In this study, anticandidal activity of chitosan silver nanocomposite (CAgNC) was tested against C. albicans Minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of CAgNC were determined as 25 and 100 μg/ml, respectively. Electron microscopic image results confirmed the ultrastructural cell wall deformities and injuries caused by CAgNC. Propidium iodide (PI) penetration into the CAgNC treated cells could be considered as an evidence for loss of cell membrane integrity and cell death at MFC. Level of intracellular reactive oxygen species (ROS) was increased, while cell viability was decreased with the increased of CAgNC concentrations. In our protein profile results, several induced proteins were observed under CAgNC treatment, and they could be related to multidrug and stress resistant proteins such as CDR1 (55 kDa) and CaHSP70 based on the protein band size. CAgNC mediated cell wall damage, loss of cell membrane integrity, elevated ROS level, and associated oxidative stress have been identified as the main causative factors for the anticandidal activity. Overall results from our study indicated that CAgNC could affect negatively on physiological and biochemical functions of C. albicans suggesting CAgNC as a potential alternative for antifungal chemotherapy.

  3. Patterns of in vitro activity of itraconazole and imidazole antifungal agents against Candida albicans with decreased susceptibility to fluconazole from Spain.

    PubMed

    Martinez-Suarez, J V; Rodriguez-Tudela, J L

    1995-07-01

    Two groups of recent clinical isolates of Candida albicans consisting of 101 isolates for which fluconazole MICs were < or = 0.5 microgram/ml (n = 50) and > or = 4.0 micrograms/ml (n = 51), respectively, were compared for their susceptibilities to fluconazole, clotrimazole, miconazole, ketoconazole, and itraconazole. Susceptibility tests were performed by a photometer-read broth microdilution method with an improved RPMI 1640 medium supplemented with 18 g of glucose per liter (RPMI-2% glucose; J. L. Rodríguez-Tudela and J. V. Martínez-Suárez, Antimicrob. Agents Chemother. 38:45-48, 1994). Preparation of drugs, basal medium, and inocula was done by the recommendations of the National Committee for Clinical Laboratory Standards. The MIC endpoint was calculated objectively from the turbidimetric data read at 24 h as the lowest drug concentration at which growth was just equal to or less than 20% of that in the positive control well (MIC 80%). In vitro susceptibility testing separated azole-susceptible strains from the strains with decreased susceptibilities to azoles if wide ranges of concentrations (20 doubling dilutions) were used for ketoconazole, miconazole, and clotrimazole. By comparison with isolates for which fluconazole MICs were < or = 0.5 microgram/ml, those isolates for which fluconazole MICs were > or = 4.0 micrograms/ml were in general less susceptible to other azole drugs, but different patterns of decreased susceptibility were found, including uniform increases in the MICs of all azole derivatives, higher MICs of several azoles but not others, and elevated MICs of fluconazole only. On the other hand, decreased susceptibility to any other azole drug was never found among strains for which MICs of fluconazole were lower.

  4. The Role of Topical Antifungal Therapy for Onychomycosis and the Emergence of Newer Agents

    PubMed Central

    2014-01-01

    Onychomycosis is a common infection of the nail unit that is usually caused by a dermatophyte (tinea unguium) and most frequently affects toenails in adults. In most cases, onychomycosis is associated with limited treatment options that are effective in achieving complete clearance in many cases. In addition, recurrence rates are high in the subset of treated patients who have been effectively cleared, usually with an oral antifungal agent. There has been a conspicuous absence of medical therapies approved in the United States since the introduction of topical ciclopirox (8% nail lacquer), with no new effective agents introduced for more than 10 years. Fortunately, newer agents and formulations have been under formal development. While patients might prefer a topical therapy, efficacy with ciclopirox 8% nail lacquer, the only available agent until the very recent approval of efinaconazole 10% solution, has been disappointing. The poor therapeutic outcomes achieved with ciclopirox 8% nail lacquer were not unexpected as the cure rates achieved in the clinical trials were unimpressive, despite concomitant nail debridement, which was an integral part of the pivotal trials with ciclopirox 8% nail lacquer. Efinaconazole 10% solution and tavaborole 5% solution are new topical antifungals specifically developed for the treatment of dermatophyte onychomycosis. In Phase 3 clinical trials, both newer agents were applied once daily for 48 weeks without concomitant nail debridement. Mycologic cure rates with efinaconazole 10% solution are markedly superior to what was achieved with ciclopirox 8% nail lacquer. To add, they appear to be nearly comparable to those achieved with oral itraconazole in pivotal clinical trials. However, it is important to remember that direct comparisons between different studies are not conclusive, are not generally considered to be scientifically sound, and may not be entirely accurate due to differences in study design and other factors. Well

  5. Past, Recent Progresses and Future Perspectives of Nanotechnology Applied to Antifungal Agents.

    PubMed

    Roque, Luís; Molpeceres, Jesús; Reis, Cláudia; Rijo, Patrícia; Reis, Catarina Pinto

    2017-02-01

    Candida species remain a significant cause of nosocomial bloodstream infections, associated with prolonged hospital stay in the ICU and high healthcare cost. The incidence of Candida is very high in certain risk groups of patients (AIDS, diabetes, cancer, etc.). Recent developments of nanotechnology have strongly contributed to the design of new multifunctional drug carriers that improve drug bioavailability through a controlled and prolonged release profile or even through a more specific targeted delivery of the antifungal agent. Those types of systems have strongly increased with a progressive generation of new structures, permitting the conjunction of new materials, biomolecules, physical and chemical techniques, for better outcomes. Nanotechnology shows expanded possibilities within the medical field and in the case of the yeast infections it may overcome several issues related with the fungal proliferation or higher inhibition of the pathogen causing the infection. This review covers a period of the most representative research of Candidiasis since 1993 to the present.

  6. Sparfloxacin-metal complexes as antifungal agents - Their synthesis, characterization and antimicrobial activities

    NASA Astrophysics Data System (ADS)

    Sultana, Najma; Arayne, M. Saeed; Gul, Somia; Shamim, Sana

    2010-06-01

    Metal complexes with the third-generation quinolone antibacterial agent sparfloxacin (SPFX) or 5-amino-1-cyclopropyl-7-(cis-3,5-dimethyl-1-piperazinyl)-6,8,di-fluoro-1-4-dihydro-4-oxo-3-quinocarboxylic acid have been synthesized and characterized with physicochemical and spectroscopic techniques such as TLC, IR, NMR and elemental analyses. In these complexes, sparfloxacin acts as bidentate deprotonated ligands bound to the metal through the pyridone oxygen and one carboxylate oxygen. The antimicrobial activity of these complexes has been evaluated against four Gram-positive and seven Gram-negative bacteria. Antifungal activity against five different fungi has been evaluated and compared with reference drug sparfloxacin. Fe 2+-SPFX and Cd 2+-SPFX complexes showed remarkable potency as compared to the parent drug.

  7. Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic.

    PubMed

    Pace, Jennifer R; DeBerardinis, Albert M; Sail, Vibhavari; Tacheva-Grigorova, Silvia K; Chan, Kelly A; Tran, Raymond; Raccuia, Daniel S; Wechsler-Reya, Robert J; Hadden, M Kyle

    2016-04-28

    Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.

  8. Lipopeptides as the Antifungal and Antibacterial Agents: Applications in Food Safety and Therapeutics

    PubMed Central

    Meena, Khem Raj; Kanwar, Shamsher S.

    2015-01-01

    A lot of crops are destroyed by the phytopathogens such as fungi, bacteria, and yeast leading to economic losses to the farmers. Members of the Bacillus genus are considered as the factories for the production of biologically active molecules that are potential inhibitors of growth of phytopathogens. Plant diseases constitute an emerging threat to global food security. Many of the currently available antimicrobial agents for agriculture are highly toxic and nonbiodegradable and thus cause extended environmental pollution. Moreover, an increasing number of phytopathogens have developed resistance to antimicrobial agents. The lipopeptides have been tried as potent versatile weapons to deal with a variety of phytopathogens. All the three families of Bacillus lipopeptides, namely, Surfactins, Iturins and Fengycins, have been explored for their antagonistic activities towards a wide range of phytopathogens including bacteria, fungi, and oomycetes. Iturin and Fengycin have antifungal activities, while Surfactin has broad range of potent antibacterial activities and this has also been used as larvicidal agent. Interestingly, lipopeptides being the molecules of biological origin are environmentally acceptable. PMID:25632392

  9. Otomycosis in the north of Iran: common pathogens and resistance to antifungal agents.

    PubMed

    Nemati, Shadman; Hassanzadeh, Rasool; Khajeh Jahromi, Sina; Delkhosh Nasrollah Abadi, Azimeh

    2014-05-01

    Otomycosis as a kind of external otitis can be caused by various species of fungi. To use the appropriate treatment, it is necessary to identify the causal agent of otomycosis. The aim of this study was to determine the pathogens that caused otomycosis and also the efficacy of different antifungal agents. 100 patients with diagnosis of otomycosis/otitis extern were entered in this study. Bacterial culture was performed by eosin methylene blue agar, blood agar; and Sabouraud dextrose agar was used to culture the fungal agents. Minimum inhibitory concentration test also was performed to determine the efficacy of Clotrimazole, Fluconazole, Ketoconazole and Nystatin on the fungal pathogens. Otomycosis was confirmed in 43% of patients by positive culture. The most prevalent fungal pathogen was Aspergillus niger which was sensitive to Clotrimazole, Fluconazole, Ketoconazole. Candida albicans was sensitive to all drugs, in which, the most sensitivity was due to fluconazole. The most frequent fungal pathogen in our otomycosis cases is A. niger, and most of fungi that caused otomycosis are sensitive to clotrimazole.

  10. In vitro susceptibility testing of dermatophytes isolated in Goiania, Brazil, against five antifungal agents by broth microdilution method.

    PubMed

    Araújo, Crystiane Rodrigues; Miranda, Karla Carvalho; Fernandes, Orionalda de Fatima Lisboa; Soares, Ailton José; Silva, Maria do Rosário Rodrigues

    2009-01-01

    The antifungal activities of fluconazole, itraconazole, ketoconazole, terbinafine and griseofulvin were tested by broth microdilution technique, against 60 dermatophytes isolated from nail or skin specimens from Goiania city patients, Brazil. In this study, the microtiter plates were incubated at 28 masculineC allowing a reading of the minimal inhibitory concentration (MIC) after four days of incubation for Trichophyton mentagrophytes and five days for T. rubrum and Microsporum canis. Most of the dermatophytes had uniform patterns of susceptibility to the antifungal agents tested. Low MIC values as 0.03 microg/mL were found for 33.3%, 31.6% and 15% of isolates for itraconazole, ketoconazole and terbinafine, respectively.

  11. New N,N,N',N'-tetradentate Pyrazoly Agents: Synthesis and Evaluation of their Antifungal and Antibacterial Activities.

    PubMed

    Abrigach, Farid; Bouchal, Btissam; Riant, Olivier; Macé, Yohan; Takfaoui, Abdelilah; Radi, Smaail; Oussaid, Abdelouahad; Bellaoui, Mohammed; Touzani, Rachid

    2016-01-01

    A new library of N,N,N',N' -tetradentate pyrazoly compounds containing a pyrazole moiety was synthesized by the condensation of (3,5-dimethyl-1H-pyrazol-1-yl)methanol 2a or (1H-pyrazol-1-yl)methanol 2b with a series of primary diamines in refluxed acetonitrile for 6h. The antifungal activity against the budding yeast Saccharomyces cerevisiae, as well as the antibacterial activity against Escherichia coli of these new tetradentate ligands were studied. We found that these tetradentate ligands act specifically as antifungal agents and lack antibacterial activity. Their biological activities depend on the nature of the structure of the compounds.

  12. Dynamics of in vitro acquisition of resistance by Candida parapsilosis to different azoles.

    PubMed

    Pinto e Silva, Ana Teresa; Costa-de-Oliveira, Sofia; Silva-Dias, Ana; Pina-Vaz, Cidália; Rodrigues, Acácio Gonçalves

    2009-06-01

    Candida parapsilosis is a common isolate from clinical fungal infectious episodes. Resistance of C. parapsilosis to azoles has been increasingly reported. To analyse the development of resistance in C. parapsilosis, four azole-susceptible clinical strains and one American Type Culture Collection type strain were cultured in the presence of fluconazole, voriconazole and posaconazole at different concentrations. The isolates developed variable degrees of azole resistance according to the antifungal used. Fluconazole was the fastest inducer while posaconazole was the slowest. Fluconazole and voriconazole induced resistance to themselves and each other, but not to posaconazole. Posaconazole induced resistance to all azoles. Developed resistance was stable; it could be confirmed after 30 days of subculture in drug-free medium. Azole-resistant isolates revealed a homogeneous population structure; the role of azole transporter efflux pumps was minor after evaluation by microdilution and cytometric assays with efflux pump blockers (verapamil, ibuprofen and carbonyl cyanide 3-chloro-phenylhydrazone). We conclude that the rapid development of azole resistance occurs by a mechanism that might involve mutation of genes responsible for ergosterol biosynthesis pathway, stressed by exposure to antifungals.

  13. Ketoconazole, an antifungal agent, protects against adiposity induced by a cafeteria diet.

    PubMed

    Campión, J; Martínez, J A

    2004-07-01

    Ketoconazole, an anti-glucocorticoid agent, is widely used in humans as an antifungal agent. It inhibits ergosterol synthesis and reduces cortisol levels in the treatment of Cushing's Syndrome. The aim of this work was to study the drug's preventive potential against adiposity induced by a high-fat cafeteria diet in rats. Female Wistar rats were fed on standard pelleted diet or cafeteria diet during 42 days in the presence or absence of an oral treatment with ketoconazole (24 mg/kg of body weight). The cafeteria diet increased energy intake and body weight. In addition, this high-fat diet increased body-fat weight and adipose tissue depots analyzed. Interestingly, ketoconazole was able to protect against increased total body fat and adipose depot enlargement induced after cafeteria-diet feeding. Moreover, ex vivo isoproterenol-induced lipolysis was reduced in adipocytes from cafeteria-fed animals; this decrease was reverted by treatment with ketoconazole. Thus, ketoconazole was able to protect against adiposity induced by a cafeteria diet, revealing an interaction between fat intake and glucocorticoids on adipose deposition.

  14. QuBiLs-MAS method in early drug discovery and rational drug identification of antifungal agents.

    PubMed

    Medina Marrero, R; Marrero-Ponce, Y; Barigye, S J; Echeverría Díaz, Y; Acevedo-Barrios, R; Casañola-Martín, G M; García Bernal, M; Torrens, F; Pérez-Giménez, F

    2015-01-01

    The QuBiLs-MAS approach is used for the in silico modelling of the antifungal activity of organic molecules. To this effect, non-stochastic (NS) and simple-stochastic (SS) atom-based quadratic indices are used to codify chemical information for a comprehensive dataset of 2478 compounds having a great structural variability, with 1087 of them being antifungal agents, covering the broadest antifungal mechanisms of action known so far. The NS and SS index-based antifungal activity classification models obtained using linear discriminant analysis (LDA) yield correct classification percentages of 90.73% and 92.47%, respectively, for the training set. Additionally, these models are able to correctly classify 92.16% and 87.56% of 706 compounds in an external test set. A comparison of the statistical parameters of the QuBiLs-MAS LDA-based models with those for models reported in the literature reveals comparable to superior performance, although the latter were built over much smaller and less diverse datasets, representing fewer mechanisms of action. It may therefore be inferred that the QuBiLs-MAS method constitutes a valuable tool useful in the design and/or selection of new and broad spectrum agents against life-threatening fungal infections.

  15. Low molecular weight chitosan is an effective antifungal agent against Botryosphaeria sp. and preservative agent for pear (Pyrus) fruits.

    PubMed

    Wang, Yunguang; Li, Bin; Zhang, Xuedan; Peng, Nan; Mei, Yuxia; Liang, Yunxiang

    2017-02-01

    Antifungal activity and preservative effect of a low molecular weight chitosan (LMWC) sample, derived from chitosan by enzymatic hydrolysis, were investigated in vitro and in vivo. A pathogenic fungal strain was isolated from decayed pear (Pyrus bretschneideri cv. "Huangguan") fruit and identified as Botryosphaeria sp. W-01. LMWC was shown to strongly inhibit W-01 growth based on studies of minimum inhibitory concentration (MIC) and effects on mycelial biomass and radial growth of the fungus. LMWC treatment of W-01 cells reduced ergosterol synthesis and mitochondrial membrane potential (ΔY), early events of apoptosis. Transmission electron microscopy and confocal laser scanning microscopy studies revealed that LMWC penetrated inside W-01 hyphae, thereby inducing ultrastructural damage. LMWC coating had a significant preservative effect on wounded and nonwounded pear fruits, by inhibiting postharvest decay and browning processes. LMWC activated several defense-related enzymes (polyphenol oxidase, peroxidase, chitinase), maintained nutritional value, and slowed down weight loss. Our findings indicate the strong potential of LMWC as a natural preservative agent for fruits and vegetables.

  16. Lipidomics and in Vitro Azole Resistance in Candida albicans

    PubMed Central

    Singh, Ashutosh; Mahto, Kaushal Kumar

    2013-01-01

    Abstract We have shown earlier that fluconazole (FLC) stress induces global changes in the lipidome of Candida albicans in clinically adapted isolates. However, several laboratories have developed adapted in vitro FLC resistant strains of C. albicans to study azole resistance mechanisms. This study aimed to identify the lipid changes associated with FLC resistance in these in vitro adapted isolates. Using comparative lipidomics and principal component and discriminant analyses, we observed gradual changes in several lipid classes and molecular species upon FLC exposure of in vitro resistant C. albicans strains. Although the lipid imprint of FLC in vitro resistant isolates was very distinct from that of clinical isolates of C. albicans, the overall changes in lipid class compositions were similar in both cases. For example, an increased sterol content and depleted sphingolipid levels were the salient features of FLC resistance in both conditions. Taken together, it appears that the overall cellular lipid homeostasis is a critical factor in the observed FLC resistance and in handling FLC stress in both clinical and laboratory situations. The new observations reported herein have implications for more efficacious antifungal drug development as well as understanding host–infectious agent interactions in postgenomics microbiology practice. PMID:23374108

  17. Augmenting antifungal activity of oxidizing agent with kojic acid: Control of Penicillium strains infecting crops

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Oxidative treatment is a strategy for preventing Penicillium contamination in foods or crops. Antifungal efficacy of oxidant [hydrogen peroxide (H2O2)], biotic effector [kojic acid (KA)] and abiotic stress (heat), alone or in combination, was investigated in Penicillium. The levels of antifungal int...

  18. Progressive development in experimental models of transungual drug delivery of anti-fungal agents.

    PubMed

    Thatai, P; Tiwary, A K; Sapra, B

    2016-02-01

    Pre-clinical development comprises of different procedures that relate drug discovery in the laboratory for commencement of human clinical trials. Pre-clinical studies can be designed to recognize a lead candidate from a list to develop the procedure for scale-up, to choose the unsurpassed formulation, to determine the frequency, and duration of exposure; and eventually make the foundation of the anticipated clinical trial design. The foremost aim in the pharmaceutical research and industry is the claim of drug product quality throughout a drug's life cycle. The particulars of the pre-clinical development process for different candidates may vary; however, all have some common features. Typically in vitro, in vivo or ex vivo studies are elements of pre-clinical studies. Human pharmacokinetic in vivo studies are often supposed to serve as the 'gold standard' to assess product performance. On the other hand, when this general assumption is revisited, it appears that in vitro studies are occasionally better than in vivo studies in assessing dosage forms. The present review is compendious of different such models or approaches that can be used for designing and evaluation of formulations for nail delivery with special reference to anti-fungal agents.

  19. The use of SLN and NLC as topical particulate carriers for imidazole antifungal agents.

    PubMed

    Souto, E B; Müller, R H

    2006-05-01

    Two different imidazole antifungal agents have been used as model drugs to be incorporated into solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), once they are very well established as anti-mycotics for the treatment of topical fungal infections. Because of the high mucoadhesive properties and the strong in situ gelling properties of polyacrylic acid polymers, hydrogels prepared with those macromolecules might be a promising vehicle for imidazole-loaded lipid nanoparticles, such as the above-mentioned SLN and NLC. Thus, in this study Carbopol 934 has been selected for the preparation of semi-solid formulations based on SLN and NLC. Formulations have been stored at three different temperatures before and after particle incorporation into polyacrylate hydrogels. The particle size and the chemical stability of incorporated model drugs have been monitored by HPLC analysis for two years. On the day of production 91.7% and 98.7% of clotrimazole, but only 62.1% and 70.3% of ketoconazole have been recovered from SLN and NLC, respectively. More than 95% of clotrimazole but less than 30% of ketoconazole were detected in the developed formulations after a shelf life of two years. Those values showed to be higher than those obtained with reference emulsions of similar composition and droplet sizes. By rheological measurements a pseudoplastic behaviour with thixotropic properties has been characterized for all semi-solid systems.

  20. Azole fungicides disturb intracellular Ca2+ in an additive manner in dopaminergic PC12 cells.

    PubMed

    Heusinkveld, Harm J; Molendijk, Jeffrey; van den Berg, Martin; Westerink, Remco H S

    2013-08-01

    Humans are exposed to complex mixtures of pesticides and other compounds, mainly via food. Azole fungicides are broad spectrum antifungal compounds used in agriculture and in human and veterinary medicine. The mechanism of antifungal action relies on inhibition of CYP51, resulting in inhibition of fungal cell growth. Known adverse health effects of azole fungicides are mainly linked to CYP inhibition. Additionally, azole fungicide-induced neurotoxicity has been reported, though the underlying mechanism(s) are largely unknown. We therefore investigated the effects of a group of six azole fungicides (imazalil, flusilazole, fluconazole, tebuconazole, triadimefon, and cyproconazole) on cell viability using a combined alamar Blue/CFDA-AM assay and on oxidative stress using a H2-DCFDA fluorescent assay. As calcium plays a pivotal role in neuronal survival and functioning, effects of these six azole fungicides and binary and quaternary mixtures of azole fungicides on the intracellular calcium concentration ([Ca(2+)]i) were investigated using single-cell fluorescence microscopy in dopaminergic PC12 cells loaded with the calcium-sensitive fluorescent dye Fura-2. Only modest changes in cell viability and ROS production were observed. However, five out of six azole fungicides induced a nonspecific inhibition of voltage-gated calcium channels (VGCCs), though with varying potency. Experiments using binary IC20 and quaternary IC10 mixtures indicated that the inhibitory effects on VGCCs are additive. The combined findings demonstrate modulation of intracellular Ca(2+) via inhibition of VGCCs as a novel mode of action of azole fungicides. Furthermore, mixtures of azole fungicides display additivity, illustrating the need to take mixture effects into account in human risk assessment.

  1. Mechanism of Action of ME1111, a Novel Antifungal Agent for Topical Treatment of Onychomycosis

    PubMed Central

    Kubota, Natsuki; Takei-Masuda, Naomi; Yamada, Tsuyoshi; Maeda, Mari; Alshahni, Mohamed Mahdi; Abe, Shigeru; Tabata, Yuji; Maebashi, Kazunori

    2015-01-01

    Despite the existing treatment options for onychomycosis, there remains a strong demand for potent topical medications. ME1111 is a novel antifungal agent that is active against dermatophytes, has an excellent ability to penetrate human nails, and is being developed as a topical agent for onychomycosis. In the present study, we investigated its mechanism of action. Trichophyton mentagrophytes mutants with reduced susceptibility to ME1111 were selected in our laboratory, and genome sequences were determined for 3 resistant mutants. The inhibitory effect on a candidate target was evaluated by a spectrophotometric enzyme assay using mitochondrial fractions. Point mutations were introduced into candidate genes by a reverse genetics approach. Whole-genome analysis of the 3 selected mutants revealed point mutations in the structural regions of genes encoding subunits of succinate dehydrogenase (complex II). All of the laboratory-generated resistant mutants tested harbored a mutation in one of the subunits of succinate dehydrogenase (SdhB, SdhC, or SdhD). Most of the mutants showed cross-resistance to carboxin and boscalid, which are succinate dehydrogenase inhibitors. ME1111 strongly inhibited the succinate-2,6-dichlorophenolindophenol reductase reaction in Trichophyton rubrum and T. mentagrophytes (50% inhibitory concentrations [IC50s] of 0.029 and 0.025 μg/ml, respectively) but demonstrated only moderate inhibition of the same reaction in human cell lines. Furthermore, the target protein of ME1111 was confirmed by the introduction of point mutations causing the amino acid substitutions in SdhB, SdhC, and SdhD found in the laboratory-generated resistant mutants, which resulted in reduced susceptibility to ME1111. Thus, ME1111 is a novel inhibitor of the succinate dehydrogenase of Trichophyton species, and its mechanism of action indicates its selective profile. PMID:26596944

  2. Effects of temperature on anti-Candida activities of antifungal antibiotics.

    PubMed Central

    Odds, F C

    1993-01-01

    The relative growth (percentage of growth relative to control growth) of 767 Candida isolates representing five species was measured in microcultures at 25 and 37 degrees C. In the presence of 10(-4) M flucytosine, the distribution of relative yeast growth data indicated that Candida albicans isolates were less susceptible at 25 degrees C than at 37 degrees C, while the opposite was found with 4 x 10(-5) M amorolfine for most of the isolates tested. Repetition of the experiments at four different temperatures with 99 C. albicans isolates and five antifungal agents confirmed a direct relationship between growth inhibition and increasing temperature from 25 to 40 degrees C with amphotericin B, flucytosine, and terconazole; a strong inverse relationship between inhibition and temperature with amorolfine; and a weak inverse relationship with terbinafine. However, these relationships were not always noted with other Candida spp.: in particular, the growth of C. glabrata and C. parapsilosis isolates tended to be greater at 37 degrees C than at 25 degrees C in the presence of the azole-derivative antifungal agents itraconazole and terconazole. These findings stress the species-specific individuality of yeast susceptibility to azole antifungal agents. The results with C. albicans and amorolfine and terbinafine accord with their known in vivo efficacy in mycoses involving low-temperature superficial sites and poor activity against mycoses involving deep body sites. The data also reinforce the need for control of experimental variables such as temperature in the design of standardized yeast susceptibility tests. PMID:8494363

  3. Effects of temperature on anti-Candida activities of antifungal antibiotics.

    PubMed

    Odds, F C

    1993-04-01

    The relative growth (percentage of growth relative to control growth) of 767 Candida isolates representing five species was measured in microcultures at 25 and 37 degrees C. In the presence of 10(-4) M flucytosine, the distribution of relative yeast growth data indicated that Candida albicans isolates were less susceptible at 25 degrees C than at 37 degrees C, while the opposite was found with 4 x 10(-5) M amorolfine for most of the isolates tested. Repetition of the experiments at four different temperatures with 99 C. albicans isolates and five antifungal agents confirmed a direct relationship between growth inhibition and increasing temperature from 25 to 40 degrees C with amphotericin B, flucytosine, and terconazole; a strong inverse relationship between inhibition and temperature with amorolfine; and a weak inverse relationship with terbinafine. However, these relationships were not always noted with other Candida spp.: in particular, the growth of C. glabrata and C. parapsilosis isolates tended to be greater at 37 degrees C than at 25 degrees C in the presence of the azole-derivative antifungal agents itraconazole and terconazole. These findings stress the species-specific individuality of yeast susceptibility to azole antifungal agents. The results with C. albicans and amorolfine and terbinafine accord with their known in vivo efficacy in mycoses involving low-temperature superficial sites and poor activity against mycoses involving deep body sites. The data also reinforce the need for control of experimental variables such as temperature in the design of standardized yeast susceptibility tests.

  4. Intra-antral application of an anti-fungal agent for recurrent maxillary fungal rhinosinusitis: a case report

    PubMed Central

    2012-01-01

    Introduction Fungal infection of the paranasal sinuses is an increasingly recognized entity both in immunocompetent and immunocompromised individuals. Treatment has been via use of either surgical or medical modalities, or a combination of the two. Here, we present a case of utilization of intra-antral application of an anti-fungal agent in the management of recurrent fungal sinusitis in an indigent Nigerian patient. Case presentation We present the case of a 30-year-old West African Yoruba man, an indigent Nigerian clergyman, who presented to our facility with a history of recurrent nasal discharge (about one year), recurrent nasal blockage (about five months), and right facial swelling (about one week). After intra-nasal antrostomy for debulking with a systemic anti-fungal agent, our patient had a recurrence after four months. Our patient subsequently had an intra-antral application of flumetasone and clioquinol (Locacorten®-Vioform®) weekly for six weeks with improvement of symptoms and no recurrence after six months of follow-up. Conclusions We conclude that topical intra-antral application of anti-fungal agents is effective in patients with recurrent fungal maxillary sinusitis after surgical debulking. PMID:22905703

  5. Possible role of azole and echinocandin lock solutions in the control of Candida biofilms associated with silicone.

    PubMed

    Cateau, Estelle; Berjeaud, Jean-Marc; Imbert, Christine

    2011-04-01

    Until now, management of candidiasis related to implanted devices has remained problematic. The aim of this study was to investigate antifungal lock strategies against Candida albicans and Candida glabrata biofilms in vitro. Three antifungal agents were used against eight C. albicans and six C. glabrata clinical strains isolated from infected catheters. Caspofungin and micafungin, both echinocandins, as well as the azole posaconazole were tested. An in vitro model of Candida biofilm on 100% silicone catheters was used. Efficacy of the antifungal lock was tested against biofilms aged 12h and 5 days following exposure to caspofungin (5mg/L and 25mg/L), micafungin (5mg/L and 15 mg/L) and posaconazole (10mg/L) for 12h. Persistence of antibiofilm activity was investigated 1-3 days following drug elimination. Antifungal lock was considered effective in the event of a significant decrease (P<0.001) in the metabolic activity of the biofilm yeast. The results showed that micafungin had significant inhibitory effectiveness against young and mature C. albicans and C. glabrata biofilms. Moreover, this activity appeared to persist for up to 3 days. Caspofungin displayed similar activity against all C. albicans biofilms, but the activity was less persistent for C. glabrata biofilms. Posaconazole was less effective against C. albicans biofilms, but its activity was sustained. Echinocandin lock therapy could significantly enhance the management of candidiasis in patients with indwelling catheters by combating biofilms and enabling device maintenance in situ.

  6. Cunninghamella bertholletiae exhibits increased resistance to human neutrophils with or without antifungal agents as compared to Rhizopus spp.

    PubMed

    Simitsopoulou, Maria; Georgiadou, Elpiniki; Walsh, Thomas J; Roilides, Emmanuel

    2010-08-01

    Among Zygomycetes, Cunninghamella bertholletiae occurs less frequently as the etiologic agent of human disease but causes more aggressive, refractory, and fatal infections despite antifungal therapy. Little is known about the differential innate host response against Cunninghamella and other Zygomycetes in the presence of antifungal agents. We therefore studied the activity of human neutrophils (PMNs) alone or in combination with caspofungin, posaconazole (PSC), and voriconazole (VRC) against hyphae of Rhizopus oryzae, Rhizopus microsporus and C. bertholletiae. Hyphal damage was measured by XTT metabolic assay and release of IL-6, IL-8 and TNF-alpha from PMNs by ELISA. Cunninghamella bertholletiae was more resistant to PMN-induced hyphal damage than either Rhizopus spp. at effector:target (E:T) ratios of 1:1, 5:1 and 10:1 (P < 0.05). The hyphal damage caused by caspofungin at 0.1 microg/ml or PSC and VRC at 0.5 microg/ml with C. bertholletiae and R. oryzae and by caspofungin against R. microsporus ranged from 18-29%. The PMN-induced hyphal damage was not modulated by combination with antifungal agents. Cunninghamella bertholletiae induced significantly decreased IL-8 (P < 0.05), but increased TNF-alpha release from PMNs compared to both Rhizopus spp. (P < 0.01). No IL-6 was released from PMNs exposed to the three Zygomycetes. In comparison to R. oryzae and R. microsporus, C. bertholletiae is more resistant to PMN-induced hyphal damage with or without antifungal therapy and is more capable of suppressing release of IL-8.

  7. Azole resistance in Cryptococcus gattii from the Pacific Northwest: Investigation of the role of ERG11.

    PubMed

    Gast, Charles E; Basso, Luiz R; Bruzual, Igor; Wong, Brian

    2013-11-01

    Cryptococcus gattii is responsible for an expanding epidemic of serious infections in Western Canada and the Northwestern United States (Pacific Northwest). Some patients with these infections respond poorly to azole antifungals, and high azole MICs have been reported in Pacific Northwest C. gattii. In this study, multiple azoles (but not amphotericin B) had higher MICs for 25 Pacific Northwest C. gattii than for 34 non-Pacific Northwest C. gattii or 20 Cryptococcus neoformans strains. We therefore examined the roles in azole resistance of overexpression of or mutations in the gene (ERG11) encoding the azole target enzyme. ERG11/ACT1 mRNA ratios were higher in C. gattii than in C. neoformans, but these ratios did not differ in Pacific Northwest and non-Pacific Northwest C. gattii strains, nor did they correlate with fluconazole MICs within any group. Three Pacific Northwest C. gattii strains with low azole MICs and 2 with high azole MICs had deduced Erg11p sequences that differed at one or more positions from that of the fully sequenced Pacific Northwest C. gattii strain R265. However, the azole MICs for conditional Saccharomyces cerevisiae erg11 mutants expressing the 5 variant ERG11s were within 2-fold of the azole MICs for S. cerevisiae expressing the ERG11 gene from C. gattii R265, non-Pacific Northwest C. gattii strain WM276, or C. neoformans strains H99 or JEC21. We conclude that neither ERG11 overexpression nor variations in ERG11 coding sequences was responsible for the high azole MICs observed for the Pacific Northwest C. gattii strains we studied.

  8. Mitochondrial Complex I Is a Global Regulator of Secondary Metabolism, Virulence and Azole Sensitivity in Fungi

    PubMed Central

    Bromley, Mike; Johns, Anna; Davies, Emma; Fraczek, Marcin; Mabey Gilsenan, Jane; Kurbatova, Natalya; Keays, Maria; Kapushesky, Misha; Gut, Marta; Gut, Ivo; Denning, David W.; Bowyer, Paul

    2016-01-01

    Recent estimates of the global burden of fungal disease suggest that that their incidence has been drastically underestimated and that mortality may rival that of malaria or tuberculosis. Azoles are the principal class of antifungal drug and the only available oral treatment for fungal disease. Recent occurrence and increase in azole resistance is a major concern worldwide. Known azole resistance mechanisms include over—expression of efflux pumps and mutation of the gene encoding the target protein cyp51a, however, for one of the most important fungal pathogens of humans, Aspergillus fumigatus, much of the observed azole resistance does not appear to involve such mechanisms. Here we present evidence that azole resistance in A. fumigatus can arise through mutation of components of mitochondrial complex I. Gene deletions of the 29.9KD subunit of this complex are azole resistant, less virulent and exhibit dysregulation of secondary metabolite gene clusters in a manner analogous to deletion mutants of the secondary metabolism regulator, LaeA. Additionally we observe that a mutation leading to an E180D amino acid change in the 29.9 KD subunit is strongly associated with clinical azole resistant A. fumigatus isolates. Evidence presented in this paper suggests that complex I may play a role in the hypoxic response and that one possible mechanism for cell death during azole treatment is a dysfunctional hypoxic response that may be restored by dysregulation of complex I. Both deletion of the 29.9 KD subunit of complex I and azole treatment alone profoundly change expression of gene clusters involved in secondary metabolism and immunotoxin production raising potential concerns about long term azole therapy. PMID:27438017

  9. Mitochondrial Complex I Is a Global Regulator of Secondary Metabolism, Virulence and Azole Sensitivity in Fungi.

    PubMed

    Bromley, Mike; Johns, Anna; Davies, Emma; Fraczek, Marcin; Mabey Gilsenan, Jane; Kurbatova, Natalya; Keays, Maria; Kapushesky, Misha; Gut, Marta; Gut, Ivo; Denning, David W; Bowyer, Paul

    2016-01-01

    Recent estimates of the global burden of fungal disease suggest that that their incidence has been drastically underestimated and that mortality may rival that of malaria or tuberculosis. Azoles are the principal class of antifungal drug and the only available oral treatment for fungal disease. Recent occurrence and increase in azole resistance is a major concern worldwide. Known azole resistance mechanisms include over-expression of efflux pumps and mutation of the gene encoding the target protein cyp51a, however, for one of the most important fungal pathogens of humans, Aspergillus fumigatus, much of the observed azole resistance does not appear to involve such mechanisms. Here we present evidence that azole resistance in A. fumigatus can arise through mutation of components of mitochondrial complex I. Gene deletions of the 29.9KD subunit of this complex are azole resistant, less virulent and exhibit dysregulation of secondary metabolite gene clusters in a manner analogous to deletion mutants of the secondary metabolism regulator, LaeA. Additionally we observe that a mutation leading to an E180D amino acid change in the 29.9 KD subunit is strongly associated with clinical azole resistant A. fumigatus isolates. Evidence presented in this paper suggests that complex I may play a role in the hypoxic response and that one possible mechanism for cell death during azole treatment is a dysfunctional hypoxic response that may be restored by dysregulation of complex I. Both deletion of the 29.9 KD subunit of complex I and azole treatment alone profoundly change expression of gene clusters involved in secondary metabolism and immunotoxin production raising potential concerns about long term azole therapy.

  10. Synthesis and screening of antibacterial and antifungal activity of 5-chloro-1,3-benzoxazol-2(3 h)-one derivatives

    PubMed Central

    2012-01-01

    Background An antibacterial is a substance that either kills bacteria or slows their growth. Antifungal are the agents that use drugs for treatment of fungal infections. 5-Chloro-1,3-benzoxazol-2(3 H)-one (5-Chloro Benzoxazolinone) contains an azole ring structure. Numbers of azole compounds are reported as antibacterial and antifungal agents. Benzoxazolinones naturally occur in plants. They play a role as defense compounds against bacteria, fungi, and insects. Results In this article, synthesis of six Benzoxazolinone derivatives with various substituents is presented. Benzoxazolinone substituted with p-aminobenzoic acids and sulphanilamide derivatives. The above both substituents are reported as potent antimicrobial agents. Attachment with azole leads to increase its potency. The other substituents are 2,4-dichlorobezylchloride. The same rings are found in miconazole and this may lead to increase its antifungal activity. Fluconazole also contains triazole moiety and triazole is having other numbers of activity like antimicrobial, anti-inflammatory, local anesthetic, antiviral, anticancer, antimalarial, etc. Here, there is a substitution for azole ring at 5-Chloro position which might increase antibacterial and antifungal activity. The synthesis and interpretation of six final compounds and three intermediates are presented in this article. Synthesis of 5-Chloro Benzoxazolinone derivatives substituted with Halogenated rings, sulfonated and benzylated derivatives and azole derivatives. There is a synthesis of P2A, P2B, P4A, P4B, P5A, and P6A compounds and their structures were characterized by UV–Visible, IR, MASS spectroscopy, and NMR spectroscopy. Conclusions The antibacterial activity of all six compounds is measured against various Gram-positive and Gram-negative bacteria and against fungi. Compounds P4A and P4B have good antibacterial and antifungal activity, half of the Ampicillin and Cephalexin. P4A, P4B, P6A have good activity against Staphylococcus aureus

  11. Imidazole clubbed 1,3,4-oxadiazole derivatives as potential antifungal agents.

    PubMed

    Wani, Mohmmad Younus; Ahmad, Aijaz; Shiekh, Rayees Ahmad; Al-Ghamdi, Khalaf J; Sobral, Abilio J F N

    2015-08-01

    A series of compounds in which 2-(4-ethyl-2-pyridyl)-1H-imidazole was clubbed with substituted 1,3,4-oxadiazole was synthesized and subjected to antifungal activity evaluation. In vitro assays indicated that several clubbed derivatives had excellent antifungal activity against different strains of laboratory and clinically isolated Candida species. Structural Activity Relationship (SAR) studies revealed that the presence and position of substituents on the phenyl ring of the 1,3,4-oxadiazole unit, guides the antifungal potential of the compounds, where compound 4b, 4c and 4g were found to be active against all the tested fungal strains. Impairment of ergosterol biosynthesis upon the concomitant treatment of 4b, 4c and 4g, revealed the possible mechanisms of antifungal action of these compounds. Inhibitors snugly fitting the active site of the target enzyme, as revealed by molecular docking studies, may well explain their excellent inhibitory activity.

  12. Oxygenated monoterpenes-rich volatile oils as potential antifungal agents for dermatophytes.

    PubMed

    Dias, N; Dias, M C; Cavaleiro, C; Sousa, M C; Lima, N; Machado, M

    2017-02-01

    Essential oils (EOs) extracted from Lavandula luisieri and Cymbopogon citratus were tested for their antifungal activity against ten clinical isolates of dermatophytes isolated from cases of tinea pedis. Inhibition of conidial germination and antifungal drug/EO combination assay were tested on two ATCC reference strains of Trichophyton rubrum and Trichophyton mentagrophytes. EOs were characterised by high amount of oxygenated monoterpenes in their composition. Strong antifungal activity was observed for the majority of clinical strains, and fungicidal activity was demonstrated. Positive interaction between L. luisieri EO combined with terbinafine was observed against terbinafine-resistant strain (Tr ATCC MYA-4438). Significative reduction of the germination was observed above 100 μg mL(-1). Both oils were safe to macrophage mammalian cells at tested concentration. This study describes the antifungal activity of L. luisieri and C. citratus EOs against dermatophytes, which could be useful in designing new formulations for topical treatments.

  13. Self-assembled cardanol azo derivatives as antifungal agent with chitin-binding ability.

    PubMed

    Mahata, Denial; Mandal, Santi M; Bharti, Rashmi; Gupta, Vinay Krishna; Mandal, Mahitosh; Nag, Ahindra; Nando, Golok B

    2014-08-01

    Cardanol is a non-isoprenoic phenolic lipid-mixture of distilled cashew nut shell liquid obtained from Anacardium occidentale. Herein, cardanol is purified from cashew nut shell liquid (CNSL) and synthesized to new compounds with different azo amphiphiles. These synthesized compounds are allowed to self-assembled in hydrophobic environment and checked antifungal activity against Candida albicans. Self-assembled structure of CABA showed higher antifungal activity (16μg/mL) and chitin-binding ability in comparison to CAP and CANB. Furthermore, the self-assembled azo amphiphiles are immobilized with silver ions to prepare hydrogel which showed eight folds enhanced antifungal activity. Toxicity is reduced by several folds of self-assembled or hydrogel structure in comparison to pure compounds. Thus, the self-assembled structure of amphiphiles and their hydrogels have been found to be new macromolecules of interest with potential use as antifungal drugs.

  14. Evaluation of Antifungal Activity and Mode of Action of New Coumarin Derivative, 7-Hydroxy-6-nitro-2H-1-benzopyran-2-one, against Aspergillus spp.

    PubMed Central

    Guerra, Felipe Queiroga Sarmento; de Araújo, Rodrigo Santos Aquino; de Sousa, Janiere Pereira; Pereira, Fillipe de Oliveira; Mendonça-Junior, Francisco J. B.; Barbosa-Filho, José M.; de Oliveira Lima, Edeltrudes

    2015-01-01

    Aspergillus spp. produce a wide variety of diseases. For the treatment of such infections, the azoles and Amphotericin B are used in various formulations. The treatment of fungal diseases is often ineffective, because of increases in azole resistance and their several associated adverse effects. To overcome these problems, natural products and their derivatives are interesting alternatives. The aim of this study was to examine the effects of coumarin derivative, 7-hydroxy-6-nitro-2H-1-benzopyran-2-one (Cou-NO2), both alone and with antifungal drugs. Its mode of action against Aspergillus spp. Cou-NO2 was tested to evaluate its effects on mycelia growth and germination of fungal conidia of Aspergillus spp. We also investigated possible Cou-NO2 action on cell walls (0.8 M sorbitol) and on Cou-NO2 to ergosterol binding in the cell membrane. The study shows that Cou-NO2 is capable of inhibiting both the mycelia growth and germination of conidia for the species tested, and that its action affects the structure of the fungal cell wall. At subinhibitory concentration, Cou-NO2 enhanced the in vitro effects of azoles. Moreover, in combination with azoles (voriconazole and itraconazole) Cou-NO2 displays an additive effect. Thus, our study supports the use of coumarin derivative 7-hydroxy-6-nitro-2H-1-benzopyran-2-one as an antifungal agent against Aspergillus species. PMID:26175794

  15. In Vitro Antifungal Activity of ME1111, a New Topical Agent for Onychomycosis, against Clinical Isolates of Dermatophytes

    PubMed Central

    Isham, N.; Long, L.

    2015-01-01

    The treatment of onychomycosis has improved considerably over the past several decades following the introduction of the oral antifungals terbinafine and itraconazole. However, these oral agents suffer from certain disadvantages, including drug interactions and potential liver toxicity. Thus, there is a need for new topical agents that are effective against onychomycosis. ME1111 is a novel selective inhibitor of succinate dehydrogenase (complex II) of dermatophyte species, whose small molecular weight enhances its ability to penetrate the nail plate. In this study, we determined the antifungal activity of ME1111 against dermatophyte strains, most of which are known to cause nail infections, as measured by the MIC (n = 400) and the minimum fungicidal concentration (MFC) (n = 300). Additionally, we examined the potential for resistance development in dermatophytes (n = 4) following repeated exposure to ME1111. Our data show that the MIC90 of ME1111 against dermatophyte strains was 0.25 μg/ml, which was equivalent to that of the comparators amorolfine and ciclopirox (0.25 and 0.5 μg/ml, respectively). ME1111 was fungicidal at clinically achievable concentrations against dermatophytes, and its MFC90s against Trichophyton rubrum and Trichophyton mentagrophytes were 8 μg/ml, comparable to those of ciclopirox. Furthermore, ME1111, as well as ciclopirox, did not induce resistance in 4 dermatophytes tested. Our studies show that ME1111 possesses potent antifungal activity and suggest that it has low potential for the development of resistance in dermatophytes. PMID:26055386

  16. Synthesis and evaluation of α-Ag2WO4 as novel antifungal agent

    NASA Astrophysics Data System (ADS)

    Foggi, Camila C.; Fabbro, Maria T.; Santos, Luís P. S.; de Santana, Yuri V. B.; Vergani, Carlos E.; Machado, Ana L.; Cordoncillo, Eloisa; Andrés, Juan; Longo, Elson

    2017-04-01

    Because of the need for new antifungal materials with greater potency, microcrystals of α-Ag2WO4, a complex metal oxide, have been synthetized by a simple co-precipitation method, and their antifungal activity against Candida albicans has been investigated. A theoretical model based on clusters that are building blocks of α-Ag2WO4 has been proposed to explain the experimental results.

  17. Exopolysaccharide matrix of developed Candida albicans biofilms after exposure to antifungal agents.

    PubMed

    da Silva, Wander José; Gonçalves, Letícia Machado; Seneviratne, Jayampath; Parahitiyawa, Nipuna; Samaranayake, Lakshman Perera; Del Bel Cury, Altair Antoninha

    2012-01-01

    This study aimed to evaluate the effects of fluconazole or nystatin exposure on developed Candida albicans biofilms regarding their exopolysaccharide matrix. The minimal inhibitory concentration (MIC) against fluconazole or nystatin was determined for C. albicans reference strain (ATCC 90028). Poly(methlymethacrylate) resin (PMMA) specimens were fabricated according to the manufacturer's instructions and had their surface roughness measured. Biofilms were developed on specimens surfaces for 48 h and after that were exposed during 24 h to fluconazole or nystatin prepared in a medium at MIC, 10 x MIC or 100 x MIC. Metabolic activity was evaluated using an XTT assay. Production of soluble and insoluble exopolysaccharide and intracellular polysaccharides was evaluated by the phenol-sulfuric method. Confocal laser scanning microscope was used to evaluate biofilm architecture and percentage of dead/live cells. Data were analyzed statistically by ANOVA and Tukey's test at 5% significance level. The presence of fluconazole or nystatin at concentrations higher than MIC results in a great reduction of metabolic activity (p<0.001). At MIC or 10 x MIC, fluconazole showed high amounts of intracellular polysaccharides (p<0.05), but did not affect the exopolysaccharide matrix (p>0.05). The exposure to nystatin also did not alter the exopolysaccharide matrix at all the tested concentrations (p>0.05). Biofilm architecture was not affected by either of the antifungal agents (p>0.05). Nystatin promoted higher proportion of dead cells (p<0.05). It may be concluded that fluconazole and nystatin above the MIC concentration reduced the metabolic activity of C. albicans biofilms; however, they were not able to alter the exopolysaccharide matrix and biofilm architecture.

  18. Synthesis and biological evaluation of novel fluconazole analogues bearing 1,3,4-oxadiazole moiety as potent antifungal agents.

    PubMed

    Liao, Jun; Yang, Fan; Zhang, Lei; Chai, Xiaoyun; Zhao, Qingjie; Yu, Shichong; Zou, Yan; Meng, Qingguo; Wu, Qiuye

    2015-04-01

    A novel series of fluconazole based mimics incorporating 1,3,4-oxadiazole moiety were designed and synthesized. All the title compounds were characterized by (1)H-NMR, (13)C-NMR, and Q-TOF-MS. Preliminary results revealed that most of analogues exhibited significant antifungal activity against seven pathogenic fungi. Compounds 9g and 9k (MIC80 ≤ 0.125 μg/mL, respectively) were found more potent than the positive controls itraconazole and fluconazole as broad-spectrum antifungal agents. The observed docking results showed that the 1,3,4-oxadiazole moiety enhanced the affinity binding to the cytochrome P450 14α-demethylase (CYP51).

  19. Antifungal testing and high-throughput screening of compound library against Geomyces destructans, the etiologic agent of geomycosis (WNS) in bats.

    PubMed

    Chaturvedi, Sudha; Rajkumar, Sunanda S; Li, Xiaojiang; Hurteau, Gregory J; Shtutman, Michael; Chaturvedi, Vishnu

    2011-03-02

    Bats in the northeastern U.S. are affected by geomycosis caused by the fungus Geomyces destructans (Gd). This infection is commonly referred to as White Nose Syndrome (WNS). Over a million hibernating bats have died since the fungus was first discovered in 2006 in a cave near Albany, New York. A population viability analysis conducted on little brown bats (Myotis lucifugus), one of six bat species infected with Gd, suggests regional extinction of this species within 20 years. The fungus Gd is a psychrophile ("cold loving"), but nothing is known about how it thrives at low temperatures and what pathogenic attributes allow it to infect bats. This study aimed to determine if currently available antifungal drugs and biocides are effective against Gd. We tested five Gd strains for their susceptibility to antifungal drugs and high-throughput screened (HTS) one representative strain with SpectrumPlus compound library containing 1,920 compounds. The results indicated that Gd is susceptible to a number of antifungal drugs at concentrations similar to the susceptibility range of human pathogenic fungi. Strains of Gd were susceptible to amphotericin B, fluconazole, itraconazole, ketoconazole and voriconazole. In contrast, very high MICs (minimum inhibitory concentrations) of flucytosine and echinocandins were needed for growth inhibition, which were suggestive of fungal resistance to these drugs. Of the 1,920 compounds in the library, a few caused 50%--to greater than 90% inhibition of Gd growth. A number of azole antifungals, a fungicide, and some biocides caused prominent growth inhibition. Our results could provide a theoretical basis for future strategies aimed at the rehabilitation of most affected bat species and for decontamination of Gd in the cave environment.

  20. In vitro activity of the protegrin IB-367 alone and in combination compared with conventional antifungal agents against dermatophytes.

    PubMed

    Simonetti, Oriana; Silvestri, Carmela; Arzeni, Daniela; Cirioni, Oscar; Kamysz, Wojciech; Conte, Irene; Staffolani, Silvia; Orsetti, Elena; Morciano, Angela; Castelli, Pamela; Scalise, Alessandro; Kamysz, Elzbieta; Offidani, Anna Maria; Giacometti, Andrea; Barchiesi, Francesco

    2014-04-01

    The occurrence of resistance or side effects in patients receiving antifungal agents leads to failure in the treatment of mycosis. The aim of this experimental study was to investigate the in vitro effects of IB-367 alone and in combination with three standard antifungal drugs, fluconazole (FLU), itraconazole (ITRA) and terbinafine (TERB), against 20 clinical isolates of dermatophytes belonging to three species. Minimum inhibitory concentrations (MICs), minimal fungicidal concentrations (MFCs), synergy test, time-kill curves, fungal biomass (FB) and hyphal damage using 2,3-bis-(2-methoxy-4-nitro-5-sulfenylamino carbonil)-2H-tetrazolium hydroxide assay (XTT) were performed to study the efficacy of IB-367. In this study, we observed that TERB and ITRA had MICs lower values for all the strains compared to IB-367 and FLU. Synergy was found in 35%, 30% and 25% of IB-367/FLU, IB-367/ITRA and IB-367/TERB interactions respectively. IB-367 exerted a fungicidal activity against Trichophyton mentagrophytes, T. rubrum and Microsporum canis at concentrations starting from 1x MIC. At a concentration of 5x MIC, IB-367 showed the highest rates of hyphae damage for M. canis 53% and T. mentagrophytes 50%; against the same isolates it caused a reduction of 1 log of the total viable count cell hyphae damage. We propose IB-367 as a promising candidate for the future design of antifungal drugs.

  1. Screening of antifungal agents using ethanol precipitation and bioautography of medicinal and food plants.

    PubMed

    Schmourlo, Gracilene; Mendonça-Filho, Ricardo R; Alviano, Celuta Sales; Costa, Sônia S

    2005-01-15

    In the search for bioactive compounds, bioautography and ethanol precipitation of macromolecules (proteins, polysaccharides, etc.) of plant aqueous extracts were associated in an antifungal screening. Thus, the supernatants, precipitates (obtained by ethanol precipitation) and aqueous extracts were investigated of medicinal and fruit bearing plants used against skin diseases by the Brazilian population. The agar diffusion and broth dilution methods were used to assess the activity against three fungi: Candida albicans, Trichophyton rubrum and Cryptococcus neoformans. The results, evaluated by the diameter of the inhibition zone of fungal growth, indicate that six plant species, among the 16 investigated, showed significant antifungal activity. The minimal inhibitory concentration (MIC) was determined on plant extracts that showed high efficacy against the tested microorganisms. The most susceptible yeast was Trichophyton rubrum and the best antifungal activity was shown by Xanthosoma sagittifolium supernatant. The bioautography was performed only for the aqueous extracts and supernatants of those plants that showed antifungal activity against Candida albicans and Cryptococcus neoformans, using n-butanol/acetic acid/water (BAW) 8:1:1 to develop silica gel TLC plates. Clear inhibition zones were observed for aqueous extracts of Schinus molle (R(f) 0.89) and Schinus terebinthifolius (R(f) 0.80) against Candida albicans, as for supernatant of Anacardium occidentale (R(f) 0.31) against Cryptococcus neoformans. The separation of macromolecules from metabolites, as in the case of Anacardium occidentale, Solanum sp. and Xanthosoma sagittifolium, enhances antifungal activity. In other cases, the antifungal activity is destroyed, as observed for Momordica charantia, Schinus molle and Schinus terebinthifolius.

  2. [Antifungal agents in dermatophytic disease: failure of griseofulvin, ketoconazole and itraconazole].

    PubMed

    Boudghène-Stambouli, O; Mérad-Boudia, A

    1990-01-01

    The dermatophytic disease is a rare, severe affection caused by banal dermatophytes. A genetically predisposed basis could explain the frequent failure of antifungal therapeutics. We report here the case of a 28-year-old male. Despite 2 years of griseofulvin, 23 months of ketoconazole and 8 months of itraconazole, the therapeutic failure was evident: circinate herpes, papulo-nodules, vegetating plaques, ulceration, superficial and profound adenopathies, cerebral involvement, and deterioration of the general state. The correction of the immuno-deficient state combined with antifungals could be the best therapy.

  3. Plant latex: a promising antifungal agent for post harvest disease control.

    PubMed

    Sibi, G; Wadhavan, Rashmi; Singh, Sneha; Shukla, Abhilasha; Dhananjaya, K; Ravikumar, K R; Mallesha, H

    2013-12-01

    Bioactive compounds from plant latex are potential source of antifungic against post harvest pathogens. Latex from a total of seven plant species was investigated for its phytochemical and antifungal properties. Six fungi namely Aspergillus fumigatus, A. niger, A. terreus, F. solani, P. digitatum and R. arrhizus were isolated from infected fruits and vegetables and tested against various solvent extracts of latex. Analysis of latex extracts with phytochemical tests showed the presence of alkaloids, flavonoids, glycosides, phenols, saponins, steroids, tannins and terpenoids. Antifungal assay revealed the potential inhibitory activity of petroleum ether extracts against the postharvest fungal isolates. Various degree of sensitivity was observed irrespective of plant species studied with A. terreus and P. digitatum as the most susceptible ones. F. solani and A. fumigatus were moderately sensitive to the latex extracts tested. Among the plants, latex of Thevetia peruviana (75.2%) and Artocarpus heterophyllus (64.8%) were having potential antifungal activity against the isolates followed by Manilkara zapota (51.1%). In conclusion, use of plant latex makes interest to control postharvest fungal diseases and is fitting well with the concept of safety for human health and environment.

  4. Antifungal Therapy in Hematopoietic Stem Cell Transplant Recipients.

    PubMed

    Busca, Alessandro; Pagano, Livio

    2016-01-01

    Invasive fungal infections (IFI) represent a major hindrance to the success of hematopoietic stem cell transplantation (HSCT), contributing substantially to morbidity and infection-related mortality. During the most recent years several reports indicate an overall increase of IFI among hematologic patients, in particular, invasive aspergillosis, that may be explained, at least partially, by the fact that diagnoses only suspected in the past, are now more easily established due to the application of serum biomarkers and early use of CT scan. Along with new diagnostic options, comes the recent development of novel antifungal agents that expanded the spectrum of activity over traditional treatments contributing to the successful management of fungal diseases. When introduced in 1959, Amphotericin B deoxycholate (d-AmB) was a life-saving drug, and the clinical experience over 50 years has proven that this compound is effective although toxic. Given the superior safety profile, lipid formulations of AmB have now replaced d-AmB in many circumstances. Similarly, echinocandins have been investigated as initial therapy for IA in several clinical trials including HSCT recipients, although the results were moderately disappointing leading to a lower grade of recommendation in the majority of published guidelines. Azoles represent the backbone of therapy for treating immunocompromised patients with IFI, including voriconazole and the newcomer isavuconazole; in addition, large studies support the use of mold-active azoles, namely voriconazole and posaconazole, as antifungal prophylaxis in HSCT recipients. The aim of the present review is to summarize the clinical application of antifungal agents most commonly employed in the treatment of IFI.

  5. Antifungal Therapy in Hematopoietic Stem Cell Transplant Recipients

    PubMed Central

    Busca, Alessandro; Pagano, Livio

    2016-01-01

    Invasive fungal infections (IFI) represent a major hindrance to the success of hematopoietic stem cell transplantation (HSCT), contributing substantially to morbidity and infection-related mortality. During the most recent years several reports indicate an overall increase of IFI among hematologic patients, in particular, invasive aspergillosis, that may be explained, at least partially, by the fact that diagnoses only suspected in the past, are now more easily established due to the application of serum biomarkers and early use of CT scan. Along with new diagnostic options, comes the recent development of novel antifungal agents that expanded the spectrum of activity over traditional treatments contributing to the successful management of fungal diseases. When introduced in 1959, Amphotericin B deoxycholate (d-AmB) was a life-saving drug, and the clinical experience over 50 years has proven that this compound is effective although toxic. Given the superior safety profile, lipid formulations of AmB have now replaced d-AmB in many circumstances. Similarly, echinocandins have been investigated as initial therapy for IA in several clinical trials including HSCT recipients, although the results were moderately disappointing leading to a lower grade of recommendation in the majority of published guidelines. Azoles represent the backbone of therapy for treating immunocompromised patients with IFI, including voriconazole and the newcomer isavuconazole; in addition, large studies support the use of mold-active azoles, namely voriconazole and posaconazole, as antifungal prophylaxis in HSCT recipients. The aim of the present review is to summarize the clinical application of antifungal agents most commonly employed in the treatment of IFI. PMID:27648202

  6. A D-octapeptide drug efflux pump inhibitor acts synergistically with azoles in a murine oral candidiasis infection model.

    PubMed

    Hayama, Kazumi; Ishibashi, Hiroko; Ishijima, Sanae A; Niimi, Kyoko; Tansho, Shigeru; Ono, Yasuo; Monk, Brian C; Holmes, Ann R; Harding, David R K; Cannon, Richard D; Abe, Shigeru

    2012-03-01

    Clinical management of patients undergoing treatment of oropharyngeal candidiasis with azole antifungals can be impaired by azole resistance. High-level azole resistance is often caused by the overexpression of Candida albicans efflux pump Cdr1p. Inhibition of this pump therefore represents a target for combination therapies that reverse azole resistance. We assessed the therapeutic potential of the D-octapeptide derivative RC21v3, a Cdr1p inhibitor, in the treatment of murine oral candidiasis caused by either the azole-resistant C. albicans clinical isolate MML611 or its azole-susceptible parental strain MML610. RC21v3, fluconazole (FLC), or a combination of both drugs were administered orally to immunosuppressed ICR mice at 3, 24, and 27 h after oral inoculation with C. albicans. FLC protected the mice inoculated with MML610 from oral candidiasis, but was only partially effective in MML611-infected mice. The co-application of RC21v3 (0.02 μmol per dose) potentiated the therapeutic performance of FLC for mice infected with either strain. It caused a statistically significant decrease in C. albicans cfu isolated from the oral cavity of the infected mice and reduced oral lesions. RC21v3 also enhanced the therapeutic activity of itraconazole against MML611 infection. These results indicate that RC21v3 in combination with azoles has potential as a therapy against azole-resistant oral candidiasis.

  7. Comparison of antifungal activities of various essential oils on the Phytophthora drechsleri, the causal agent of fruit decay

    PubMed Central

    Mohammadi, Ali; Hashemi, Maryam; Hosseini, Seyed Masoud

    2015-01-01

    Background and Objectives: The efficacy of Mentha piperita L, Zataria multiflora Boiss and Thymus vulgaris L essential oils (EOs) was evaluated for controlling the growth of Phytophthora drechsleri, the causative agent of damage to many crops that is consumed directly by humans. Materials and Methods: The EOs used in this study was purchased from Magnolia Co, Iran. The pour plate method in petri dishes containing Potato Dextrose Agar (PDA) was used to evaluate the antifungal properties of EOs. The minimal inhibitory concentrations (MIC), minimum fungicidal concentration (MFC) as well as mycelial growth inhibition (MGI) were measured. The IC50 value (the concentration inhibited 50% of the mycelium growth) was calculated by probit analysis. Results and Conclusion: The fungal growth was significantly reduced by increasing concentrations of tested EOs. The complete reduction was obtained with Shirazi thyme at all concentrations, whereas the complete reduction for peppermint and thyme was observed at 0.4% and 0.8% (v/v) concentrations, respectively. Meanwhile, the minimum inhibition was observed when 0.1% peppermint (MGI values of 9.37%) was used. The IC50, MIC and MFC values of Shirazi thyme was 0.053, 0.1% and 0.2%, respectively. Similarly, MIC and MFC values of peppermint and thyme were recorded 0.4% and 0.8%, respectively. The results obtained from this study may contribute to the development of new antifungal agents to protect the crops from this pathogenic fungus and many agricultural plant pathogens causing drastic crop losses. PMID:26644871

  8. Inhibition of heat-shock protein 90 enhances the susceptibility to antifungals and reduces the virulence of Cryptococcus neoformans/Cryptococcus gattii species complex.

    PubMed

    Cordeiro, Rossana de Aguiar; Evangelista, Antonio José de Jesus; Serpa, Rosana; Marques, Francisca Jakelyne de Farias; de Melo, Charlline Vládia Silva; de Oliveira, Jonathas Sales; Franco, Jônatas da Silva; de Alencar, Lucas Pereira; Bandeira, Tereza de Jesus Pinheiro Gomes; Brilhante, Raimunda Sâmia Nogueira; Sidrim, José Júlio Costa; Rocha, Marcos Fébio Gadelha

    2016-02-01

    Heat-shock proteins (Hsps) are chaperones required for the maintenance of cellular homeostasis in different fungal pathogens, playing an important role in the infectious process. This study investigated the effect of pharmacological inhibition of Hsp90 by radicicol on the Cryptococcus neoformans/Cryptococcus gattii species complex--agents of the most common life-threatening fungal infection amongst immunocompromised patients. The influence of Hsp90 inhibition was investigated regarding in vitro susceptibility to antifungal agents of planktonic and sessile cells, ergosterol concentration, cell membrane integrity, growth at 37 °C, production of virulence factors in vitro, and experimental infection in Caenorhabditis elegans. Hsp90 inhibition inhibited the in vitro growth of planktonic cells of Cryptococcus spp. at concentrations ranging from 0.5 to 2 μg ml(-1) and increased the in vitro inhibitory effect of azoles, especially fluconazole (FLC) (P < 0.05). Inhibition of Hsp90 also increased the antifungal activity of azoles against biofilm formation and mature biofilms of Cryptococcus spp., notably for Cryptococcus gattii. Furthermore, Hsp90 inhibition compromised the permeability of the cell membrane, and reduced planktonic growth at 37 °C and the capsular size of Cryptococcus spp. In addition, Hsp90 inhibition enhanced the antifungal activity of FLC during experimental infection using Caenorhabditis elegans. Therefore, our results indicate that Hsp90 inhibition can be an important strategy in the development of new antifungal drugs.

  9. Ototopical antifungals and otomycosis: a review.

    PubMed

    Munguia, Raymundo; Daniel, Sam J

    2008-04-01

    There has been an increase in the prevalence of otomycosis in recent years. This has been linked to the extensive use of antibiotic eardrops. Treatment of otomycosis is challenging, and requires a close follow-up. We present a review of the literature on otomycosis, the topical antifungals most commonly used, and discuss their ototoxic potential. Candida albicans and Aspergillus are the most commonly identified organisms. Antifungals from the Azole class seem to be the most effective, followed by Nystatin and Tolnaftate.

  10. New synthesis and biological evaluation of benzothiazole derivates as antifungal agents.

    PubMed

    Herrera Cano, Natividad; Ballari, María S; López, Abel G; Santiago, Ana N

    2015-04-15

    In search of new antifungal agrochemicals that could replace commercially available, aryl-2-mercaptobenzothiazoles were synthesized. They were prepared by two methodologies, using both photostimulated reaction and microwave assisted reaction. These reactions took place without the use of metallic catalyst by a one-pot procedure with excellent yields (70-98%). Synthesized compounds were evaluated for fungal growth inhibition against Botrytis cinerea. Most of the compounds have an excellent antifungal activity, and three of these showed a superior inhibitory effect to commercial fungicide Triadimefon. IC50 values observed for 2-(phenylthio)benzothiazole, 2-(2-chlorophenylthio)benzothiazole, and 2-(3-chlorophenyl thio)benzothiazole were 0.75, 0.69, and 0.65 μg mL(-1), respectively.

  11. Chemoenzymatic synthesis of two new halogenated coumarin glycosides as potential antifungal agents.

    PubMed

    Zhou, Liangbin; Liu, Ling; Tian, Tian; Xue, Bailin; Yu, Rongmin

    2012-10-01

    Two new potential antifungal coumarin glycosides, 6-chlorocoumarin 7-O-beta-D-glucopyranoside (1) and 7-hydroxy-4-trifluoromethyl-coumarin 5-O-beta-D-glucopyranoside (2), were synthesized via enzyme-mediated glycosylation of the respective aglycone, 6-chloro-7-hydroxycoumarin and 5,7-dihydroxy-4-trifluoromethylcoumarin, using transgenic hairy roots of Polygonum multiflorum. Instead of application of the isolated enzyme and exogenous sugar donors, hairy roots of P. multiflorum were successfully adapted as a whole-cell biocatalyst.

  12. Azole drugs are imported by facilitated diffusion in Candida albicans and other pathogenic fungi.

    PubMed

    Mansfield, Bryce E; Oltean, Hanna N; Oliver, Brian G; Hoot, Samantha J; Leyde, Sarah E; Hedstrom, Lizbeth; White, Theodore C

    2010-09-30

    Despite the wealth of knowledge regarding the mechanisms of action and the mechanisms of resistance to azole antifungals, very little is known about how the azoles are imported into pathogenic fungal cells. Here the in-vitro accumulation and import of Fluconazole (FLC) was examined in the pathogenic fungus, Candida albicans. In energized cells, FLC accumulation correlates inversely with expression of ATP-dependent efflux pumps. In de-energized cells, all strains accumulate FLC, suggesting that FLC import is not ATP-dependent. The kinetics of import in de-energized cells displays saturation kinetics with a K(m) of 0.64 μM and V(max) of 0.0056 pmol/min/10⁸ cells, demonstrating that FLC import proceeds via facilitated diffusion through a transporter rather than passive diffusion. Other azoles inhibit FLC import on a mole/mole basis, suggesting that all azoles utilize the same facilitated diffusion mechanism. An analysis of related compounds indicates that competition for azole import depends on an aromatic ring and an imidazole or triazole ring together in one molecule. Import of FLC by facilitated diffusion is observed in other fungi, including Cryptococcus neoformans, Saccharomyces cerevisiae, and Candida krusei, indicating that the mechanism of transport is conserved among fungal species. FLC import was shown to vary among Candida albicans resistant clinical isolates, suggesting that altered facilitated diffusion may be a previously uncharacterized mechanism of resistance to azole drugs.

  13. Combination of synthetic and natural products as pesticides (CSYNAP): a new class of antifungal agents.

    PubMed

    Rani, Archna; Jain, Sapna; Dureja, Prem; Tripathi, Praveen K; Singh, Kamalendra

    In the present communication some dehydrated dialdol products such as 1, 5 - Diphenyl pent - 1, 4 - diene - 3 - one (A1); 1, 9 - Diphenylnon - 1, 3, 6, 8 - tetraene - 5 - one (A2); 1, 5 - di (2 - hydroxyphenyl) pent - 1, 4 - diene - 3 - one (A3); 1, 5 - difuran pent - 1, 4 - diene - 3 - one (A4); 1, 5 - di [4 - bis (N, Ndimethyl) phenyl] pent - 1, 4 - diene - 3 - one (A5) were screened for their antifungal activity. To reduce their adverse effect on the environment, for the first time, we have attempted to screen the antifungal activity of these synthetic compounds in conjunction with selected natural products. The natural products that were used in our study include Nicotine tobaccum and Neem oil (Azadirachta indica). A set of 15 samples was tested against highly pathogenic and of extensive host range fungi Sclerotium rolfsii, Rhizactonia bataticola, Fusarium udum. The filter paper disc assay to monitor antifungal effect revealed significant and interesting results. We found that the use of the combination of natural and synthetic pesticides is more effective and environmentally healthy compared to just synthetic chemicals and/or less available natural products. These results obtained from the combined use of natural and synthetic chemicals lead us to suggest to a new class of less toxic but more effective pesticides. We call it group as CSYNAP, i. e. Combination of SYnthetic and NAtural products as Pesticides.

  14. Comparative evaluation of Etest and sensititre yeastone panels against the Clinical and Laboratory Standards Institute M27-A2 reference broth microdilution method for testing Candida susceptibility to seven antifungal agents.

    PubMed

    Alexander, Barbara D; Byrne, Terry C; Smith, Kelly L; Hanson, Kimberly E; Anstrom, Kevin J; Perfect, John R; Reller, L Barth

    2007-03-01

    To assess their utility for antifungal susceptibility testing in our clinical laboratory, the Etest and Sensititre methods were compared with the Clinical and Laboratory Standards Institute (CLSI) M27-A2 reference broth microdilution method. Fluconazole (FL), itraconazole (I), voriconazole (V), posaconazole (P), flucytosine (FC), caspofungin (C), and amphotericin B (A) were tested with 212 Candida isolates. Reference MICs were determined after 48 h of incubation, and Etest and Sensititre MICs were determined after 24 h and 48 h of incubation. Overall, excellent essential agreement (EA) between the reference and test methods was observed for Etest (95%) and Sensititre (91%). Etest showed an >or=92% EA for MICs for all drugs tested; Sensititre showed a >or=92% EA for MICs for I, FC, A, and C but 82% for FL and 85% for V. The overall categorical agreement (CA) was 90% for Etest and 88% for Sensititre; minor errors accounted for the majority of all categorical errors for both systems. Categorical agreement was lowest for Candida glabrata and Candida tropicalis with both test systems. Etest and Sensititre provided better CA at 24 h compared to 48 h for C. glabrata; however, CA for C. glabrata was <80% for FL with both test systems despite MIC determination at 24 h. Agreement between technologists for both methods was >or=98% for each agent against all organisms tested. Overall, Etest and Sensititre methods compared favorably with the CLSI reference method for determining the susceptibility of Candida. However, further evaluation of their performance for determining the MICs of azoles, particularly for C. glabrata, is warranted.

  15. Fungal peritonitis in patients undergoing peritoneal dialysis (PD) in Brazil: molecular identification, biofilm production and antifungal susceptibility of the agents.

    PubMed

    Giacobino, Juliana; Montelli, Augusto Cezar; Barretti, Pasqual; Bruder-Nascimento, Ariane; Caramori, Jacqueline Teixeira; Barbosa, Luciano; Bagagli, Eduardo

    2016-10-01

    This paper presents data on fungal peritonitis (FP) in patients undergoing peritoneal dialysis (PD) at the University Hospital of Botucatu Medical School, São Paulo, Brazil. In a total of 422 patients, 30 developed FP, from which the medical records and the fungal isolates of 23 patient cases were studied. All patients presented abdominal pain, cloudy peritoneal effluent, needed hospitalization, had the catheter removed and were treated with fluconazole or fluconazole plus 5-flucitosine; six of them died due to FP. Concerning the agents, it was observed that Candida parapsilosis was the leading species (9/23), followed by Candida albicans (5/23), Candida orthopsilosis (4/23), Candida tropicalis (3/23), Candida guilliermondii (1/23), and Kodamaea ohmeri (1/23). All the isolates were susceptible to amphotericin B, voriconazole and caspofungin whereas C. albicans isolates were susceptible to all antifungals tested. Resistance to fluconazole was observed in three isolates of C. orthopsilosis, and dose-dependent susceptibility to this antifungal was observed in two isolates of C. parapsilosis and in the K. ohmeri isolate. Biofilm production estimates were high or moderate in most isolates, especially in C. albicans species, and low in C. parapsilosis species, with a marked variation among the isolates. This Brazilian study reinforces that FP in PD is caused by a diverse group of yeasts, most prevalently C. parapsilosis sensu stricto species. In addition, they present significant variation in susceptibility to antifungals and biofilm production, thus contributing to the complexity and severity of the clinical features.

  16. [NEW ANTIFUNGAL DRUGS FOR PREVENTION AND TREATMENT OF VISCERAL MYCOSES].

    PubMed

    Pilmis, Benoît; Lortholary, Olivier; Lanternier, Fanny L

    2015-12-01

    Invasive fungal infections are increasing due to the increase in the number of at risk patients. The antifungal armamentarium has been improved the last few years with new galenic for ampoetericin B, the widening of the azole spectrum with voriconazole, poscaonazole and isavuconazole and the launch of a new antifungal class, the eschinocandins, currently represented by casoefungin and micftungin. The aim of this work is to provide an update in new antifungal drugs available.

  17. Antifungal Susceptibility Testing of Ascomycetous Yeasts Isolated from Animals

    PubMed Central

    Álvarez-Pérez, Sergio; García, Marta E.; Peláez, Teresa; Martínez-Nevado, Eva

    2016-01-01

    Recent studies suggest that antifungal resistance in yeast isolates of veterinary origin may be an underdiagnosed threat. We tested a collection of 92 ascomycetous yeast isolates that were obtained in Spain from birds, mammals and insects for antifungal susceptibility. MICs to amphotericin B and azoles were low, and no resistant isolates were detected. Despite these results, and given the potential role of animals as reservoirs of resistant strains, continuous monitoring of antifungal susceptibility in the veterinary setting is recommended. PMID:27216048

  18. Azole fungicides affect mammalian steroidogenesis by inhibiting sterol 14 alpha-demethylase and aromatase.

    PubMed

    Zarn, Jürg A; Brüschweiler, Beat J; Schlatter, Josef R

    2003-03-01

    Azole compounds play a key role as antifungals in agriculture and in human mycoses and as non-steroidal antiestrogens in the treatment of estrogen-responsive breast tumors in postmenopausal women. This broad use of azoles is based on their inhibition of certain pathways of steroidogenesis by high-affinity binding to the enzymes sterol 14-alpha-demethylase and aromatase. Sterol 14-alpha-demethylase is crucial for the production of meiosis-activating sterols, which recently were shown to modulate germ cell development in both sexes of mammals. Aromatase is responsible for the physiologic balance of androgens and estrogens. At high doses, azole fungicides and other azole compounds affect reproductive organs, fertility, and development in several species. These effects may be explained by inhibition of sterol 14-alpha-demethylase and/or aromatase. In fact, several azole compounds were shown to inhibit these enzymes in vitro, and there is also strong evidence for inhibiting activity in vivo. Furthermore, the specificity of the enzyme inhibition of several of these compounds is poor, both with respect to fungal versus nonfungal sterol 14-alpha-demethylases and versus other P450 enzymes including aromatase. To our knowledge, this is the first review on sterol 14-alpha-demethylase and aromatase as common targets of azole compounds and the consequence for steroidogenesis. We conclude that many azole compounds developed as inhibitors of fungal sterol 14-alpha-demethylase are inhibitors also of mammalian sterol 14-alpha-demethylase and mammalian aromatase with unknown potencies. For human health risk assessment, data on comparative potencies of azole fungicides to fungal and human enzymes are needed.

  19. Azole fungicides affect mammalian steroidogenesis by inhibiting sterol 14 alpha-demethylase and aromatase.

    PubMed Central

    Zarn, Jürg A; Brüschweiler, Beat J; Schlatter, Josef R

    2003-01-01

    Azole compounds play a key role as antifungals in agriculture and in human mycoses and as non-steroidal antiestrogens in the treatment of estrogen-responsive breast tumors in postmenopausal women. This broad use of azoles is based on their inhibition of certain pathways of steroidogenesis by high-affinity binding to the enzymes sterol 14-alpha-demethylase and aromatase. Sterol 14-alpha-demethylase is crucial for the production of meiosis-activating sterols, which recently were shown to modulate germ cell development in both sexes of mammals. Aromatase is responsible for the physiologic balance of androgens and estrogens. At high doses, azole fungicides and other azole compounds affect reproductive organs, fertility, and development in several species. These effects may be explained by inhibition of sterol 14-alpha-demethylase and/or aromatase. In fact, several azole compounds were shown to inhibit these enzymes in vitro, and there is also strong evidence for inhibiting activity in vivo. Furthermore, the specificity of the enzyme inhibition of several of these compounds is poor, both with respect to fungal versus nonfungal sterol 14-alpha-demethylases and versus other P450 enzymes including aromatase. To our knowledge, this is the first review on sterol 14-alpha-demethylase and aromatase as common targets of azole compounds and the consequence for steroidogenesis. We conclude that many azole compounds developed as inhibitors of fungal sterol 14-alpha-demethylase are inhibitors also of mammalian sterol 14-alpha-demethylase and mammalian aromatase with unknown potencies. For human health risk assessment, data on comparative potencies of azole fungicides to fungal and human enzymes are needed. PMID:12611652

  20. The Aspergillus fumigatus Damage Resistance Protein Family Coordinately Regulates Ergosterol Biosynthesis and Azole Susceptibility

    PubMed Central

    Song, Jinxing; Zhai, Pengfei; Zhang, Yuanwei; Zhang, Caiyun; Sang, Hong; Han, Guanzhu; Keller, Nancy P.

    2016-01-01

    ABSTRACT Ergosterol is a major and specific component of the fungal plasma membrane, and thus, the cytochrome P450 enzymes (Erg proteins) that catalyze ergosterol synthesis have been selected as valuable targets of azole antifungals. However, the opportunistic pathogen Aspergillus fumigatus has developed worldwide resistance to azoles largely through mutations in the cytochrome P450 enzyme Cyp51 (Erg11). In this study, we demonstrate that a cytochrome b5-like heme-binding damage resistance protein (Dap) family, comprised of DapA, DapB, and DapC, coordinately regulates the functionality of cytochrome P450 enzymes Erg5 and Erg11 and oppositely affects susceptibility to azoles. The expression of all three genes is induced in an azole concentration-dependent way, and the decreased susceptibility to azoles requires DapA stabilization of cytochrome P450 protein activity. In contrast, overexpression of DapB and DapC causes dysfunction of Erg5 and Erg11, resulting in abnormal accumulation of sterol intermediates and further accentuating the sensitivity of ΔdapA strains to azoles. The results of exogenous-hemin rescue and heme-binding-site mutagenesis experiments demonstrate that the heme binding of DapA contributes the decreased azole susceptibility, while DapB and -C are capable of reducing the activities of Erg5 and Erg11 through depletion of heme. In vivo data demonstrate that inactivated DapA combined with activated DapB yields an A. fumigatus mutant that is easily treatable with azoles in an immunocompromised mouse model of invasive pulmonary aspergillosis. Compared to the single Dap proteins found in Saccharomyces cerevisiae and Schizosaccharomyces pombe, we suggest that this complex Dap family regulatory system emerged during the evolution of fungi as an adaptive means to regulate ergosterol synthesis in response to environmental stimuli. PMID:26908577

  1. Induction of Resistance to Azole Drugs in Trypanosoma cruzi

    PubMed Central

    Buckner, Frederick S.; Wilson, Aaron J.; White, Theodore C.; Van Voorhis, Wesley C.

    1998-01-01

    Trypanosoma cruzi is the protozoan parasite that causes Chagas’ disease, a frequently fatal illness affecting the heart and gastrointestinal systems. An estimated 16 million to 18 million people in Latin America and 50,000 to 100,000 people in the United States are infected with this pathogen. Treatment options for T. cruzi infections are suboptimal due to the toxicities and limited effectiveness of the available drugs. Azole antimicrobial agents have been discovered to have antitrypanosomal activity by inhibition of ergosterol synthesis. The triazole itraconazole was recently shown to produce a parasitologic cure rate of 53% in chronically infected patients (W. Apt et al., Am. J. Trop. Med. Hyg. 59:133–138, 1998), a result which may lead to more use of this family of drugs for the treatment of T. cruzi infections. In the experiments reported on here, resistance to azoles was induced in vitro by serial passage of mammalian-stage parasites in the presence of fluconazole for 4 months. These parasites were cross resistant to the other azoles, ketoconazole, miconazole, and itraconazole. They remained susceptible to benznidazole and amphotericin B. The azole-resistant phenotype was stable for more than 2 months of in vitro serial passage without fluconazole. In addition, the parasites resisted treatment in mice receiving ketoconazole. The rapid development of azole resistance in T. cruzi in vitro suggests that resistance to azole drugs has the potential to occur in patients and may pose an impediment to the progress being made in the treatment of T. cruzi infection. PMID:9835521

  2. In vitro activities of five antifungal agents against 199 clinical and environmental isolates of Aspergillus flavus, an opportunistic fungal pathogen.

    PubMed

    Khodavaisy, S; Badali, H; Hashemi, S J; Aala, F; Nazeri, M; Nouripour-Sisakht, S; Sorkherizi, M S; Amirizad, K; Aslani, N; Rezaie, S

    2016-06-01

    Aspergillus flavus is the second leading cause of invasive and non-invasive aspergillosis, as well as the most common cause of fungal sinusitis, cutaneous infections, and endophthalmitis in tropical countries. Since resistance to antifungal agents has been observed in patients, susceptibility testing is helpful in defining the activity spectrum of antifungals and determining the appropriate drug for treatment. A collection of 199 clinical and environmental strains of Aspergillus flavus consisted of clinical (n=171) and environmental (n=28) were verified by DNA sequencing of the partial b-tubulin gene. MICs of amphotericin B, itraconazole, voriconazole, posaconazole, and MEC of caspofungin were determined in accordance with the Clinical and Laboratory Standards Institute M38-A2 document. Caspofungin, followed by posaconazole, exhibited the lowest minimum inhibitory concentrations (MIC). All isolates had caspofungin MEC90 (0.063μg/ml) lower than the epidemiologic cutoff values, and 3.5% of the isolates had amphotericin B MIC higher than the epidemiologic cutoff values. However, their clinical effectiveness in the treatment of A. flavus infection remains to be determined.

  3. Susceptibility to antifungal agents and genotypes of Brazilian clinical and environmental Cryptococcus gattii strains.

    PubMed

    Silva, Dayane C; Martins, Marilena A; Szeszs, Maria Walderez; Bonfietti, Lucas X; Matos, Dulcilena; Melhem, Marcia S C

    2012-04-01

    There are few reports concerning the in vitro antifungal susceptibility of clinical and environmental Cryptococcus gattii isolates. In this study, we performed polymerase chain reaction-restriction fragment length polymorphism to investigate the molecular subtypes of 50 clinical and 4 environmental Brazilian isolates of C. gattii and assessed their antifungal susceptibility for fluconazole (FLU) and amphotericin B (Amb) according to recent recommendations proposed for antifungal susceptibility testing of nonfermentative yeasts. Time-kill curve studies were performed using RPMI 1640 medium to analyze the fungicidal effect of AmB. We found 47 VGII (94%) molecular types and 3 VGI (6%) types among the clinical isolates. The environmental isolates were VGII (75%) subtype and VGI (25%) subtype. The FLU-MIC ranged from 1 to 64 mg L(-1), and MIC(50)/MIC(90) values were, respectively, 8/16 mg L(-1). For AmB, the MICs were low and homogeneous, ranging from 0.12 to 0.5 mg L(-1), for VGI or VGII. The time required to reach the fungicidal end point (99.9% killing) was 6 h for the majority of strains (64%), but viable cells of VGII were still present after 48 h of exposition. We pointed out the occurrence of high FLU-MICs for C. gattii isolates with highest values for VGII. Our data also suggest that the rate of killing of C. gattii by AmB is strain dependent, and viable cells of VGII genotype strains were still observed after an extended incubation time, addressing future studies to determine whether the in vitro fungicidal activity could be clinically relevant.

  4. Novel high-throughput screen against Candida albicans identifies antifungal potentiators and agents effective against biofilms

    PubMed Central

    LaFleur, Michael D.; Lucumi, Edinson; Napper, Andrew D.; Diamond, Scott L.; Lewis, Kim

    2011-01-01

    Objectives Microbial adhesion and biofilms have important implications for human health and disease. Candida albicans is an opportunistic pathogen which forms drug-resistant biofilms that contribute to the recalcitrance of disease. We have developed a high-throughput screen for potentiators of clotrimazole, a common therapy for Candida infections, including vaginitis and thrush. The screen was performed against C. albicans biofilms grown in microtitre plates in order to target the most resilient forms of the pathogen. Methods Biofilm growth, in individual wells of 384-well plates, was measured using the metabolic indicator alamarBlue® and found to be very consistent and reproducible. This assay was used to test the effect of more than 120 000 small molecule compounds from the NIH Molecular Libraries Small Molecule Repository, and compounds that enhanced the activity of clotrimazole or acted on the biofilms alone were identified as hits. Results Nineteen compounds (0.016% hit rate) were identified and found to cause more than 30% metabolic inhibition of biofilms compared with clotrimazole alone, which had a modest effect on biofilm viability at the concentration tested. Hits were confirmed for activity against biofilms with dose–response measurements. Several compounds had increased activity in combination with clotrimazole, including a 1,3-benzothiazole scaffold that exhibited a >100-fold improvement against biofilms of three separate C. albicans isolates. Cytotoxicity experiments using human fibroblasts confirmed the presence of lead molecules with favourable antifungal activity relative to cytotoxicity. Conclusions We have validated a novel approach to identify antifungal potentiators and completed a high-throughput screen to identify small molecules with activity against C. albicans biofilms. These small molecules may specifically target the biofilm and make currently available antifungals more effective. PMID:21393183

  5. Clerodane type diterpene as a novel antifungal agent from Polyalthia longifolia var. pendula.

    PubMed

    Bhattacharya, Asish K; Chand, Hemender R; John, Jyothis; Deshpande, Mukund V

    2015-04-13

    Bioactivity-guided chemical examination of methanolic extract of leaves of Polyalthia longifolia var. pendula led to the isolation of the active constituent, a diterpene 1 which was identified as 16α-hydroxycleroda-3,13(14)Z-dien-15,16-olide on the basis of its spectral data. Among the tested strains, diterpene 1 was found to exhibit antifungal activities having MIC90 values of 50.3, 100.6 and 201.2 μM against Candida albicans NCIM3557, Cryptococcus neoformans NCIM3542 (human pathogens) and Neurospora crassa NCIM870 (saprophyte), respectively. Initial, structure-activity-relationship (SAR) data generated by synthesizing some derivatives revealed that the double bond between C3-C4 and the free hydroxyl group at C16 are crucial for the antifungal activity of the diterpene 1. The mode of action of 1 in C. albicans is due to compromised cell membrane permeability and also probably due to disruption of cell wall structures. The red blood cell haemolysis of all the compounds (1-4) did not show any significant haemolysis and was found to be less than 15% for all the compounds when tested at highest concentration, i.e. 1200 μM. Interestingly, all the tested compounds inhibited Y-H transition in dimorphic C. albicans NCIM3557 at much lower concentration than their MIC90 values. Determination of ROS generation by diterpene 1 using DCFH-DA and DHR123 (dihydrorhodamine) staining of C. albicans NCIM3557 indicated production of intracellular ROS as a mechanism of antifungal activity.

  6. Antimicrobial peptides as potential new antifungals.

    PubMed

    Müller, F M; Lyman, C A; Walsh, T J

    1999-01-01

    Ribosomally synthesized natural antimicrobial peptides (AP) and their synthetic derivatives are small, cationic, amphipathic molecules of 12-50 amino acids with unusually broad activity spectra. These peptides kill microorganisms by a common mechanism, which involves binding to the lipid bilayer of biological membranes, forming pores, and ultimately followed by cell lysis. Several AP from mammals, amphibians, insects, plants and their synthetic derivatives demonstrate promising in vitro activity against various pathogenic fungi including azole-resistant Candida albicans strains. In addition to their antimicrobial activity, some AP such as lactoferrin, interact with a variety of host cells and can increase the activity of natural killer and lymphokine activated killer cells. Pretreatment of polymorphonuclear neutrophil leukocytes (PMN) or monocytes with these AP also may upregulate superoxide release. AP as potential new antifungal agents offer some advantages, such as rapid killing of pathogenic fungi and the difficulty to raise mutants resistant to these peptides. AP are limited by their nonselective toxicity, stability, immunogenicity and their costs of production. Potential clinical applications of AP in the future have to be further explored in preclinical and clinical studies to assess their impact as a new class of antifungals.

  7. Clinical pharmacology of antifungal agents in pediatrics: children are not small adults.

    PubMed

    Ramos-Martín, Virginia; O'Connor, Olya; Hope, William

    2015-10-01

    The optimal dosage information to improve the prognosis of invasive fungal infections in children and neonates is still limited and current dosing strategies are supported mainly by adult studies and extrapolation. Significant progress has been made to address this need in the last decade. Pre-clinical models and pharmacokinetic-pharmacodynamic (PK-PD) bridging studies supported by pediatric pharmacokinetic studies have investigated optimal dosing regimens for neonates and children. Here, we review the rationale for various antifungal regimens in infants and children.

  8. Synthesis of new triazolyl-N,N-dialkyldithiocarbamates as antifungal agents.

    PubMed

    Ozkirimli, Sumru; Apak, T Idil; Kiraz, Muammer; Yegenoglu, Yildiz

    2005-11-01

    N,N-Dialkylditihiocarbamate derivatives have been well known as broad-range fungicides. In this study, the triazole derivatives of ten new N,N-disubstituted dithiocarbamates (3a-j) were synthesized and their structures were identified by spectral and elemental analysis. Results of the antifungal activity studies showed that some of the compounds tested were active against M. canis, M. gypseum, and T. rubrum at the concentration of 12.5 microg/mL when clotrimazol was used as a standard.

  9. Species assignment and antifungal susceptibilities of black aspergilli recovered from otomycosis cases in Iran.

    PubMed

    Szigeti, Gyöngyi; Sedaghati, Ebrahim; Mahmoudabadi, Ali Zarei; Naseri, Ali; Kocsubé, Sándor; Vágvölgyi, Csaba; Varga, János

    2012-07-01

    Black aspergilli are among the main causative agents of otomycosis worldwide. In this study, the species assignment of black aspergilli isolated from otomycosis cases in Iran was carried out using sequence analysis of part of the calmodulin gene. The results indicate that Aspergillus niger is not the only black Aspergillus species involved in otomycosis cases in Iran: Aspergillus awamori and Aspergillus tubingensis are also able to cause ear infections. Antifungal susceptibility tests were carried out against five antifungal drugs including amphotericin B, fluconazole, itraconazole, ketoconazole and terbinafine. All isolates were highly susceptible to terbinafine, while they exhibited moderate susceptibilities against amphotericin B, fluconazole and ketoconazole. Aspergillus niger and A. awamori were found to have higher minimal inhibitory concentrations for azoles than A. tubingensis, in accordance with previous findings.

  10. Differential effects of antifungal agents on expression of genes related to formation of Candida albicans biofilms.

    PubMed

    Chatzimoschou, Athanasios; Simitsopoulou, Maria; Antachopoulos, Charalampos; Walsh, Thomas J; Roilides, Emmanuel

    2016-01-01

    The purpose of this study was to analyse specific molecular mechanisms involved in the intrinsic resistance of C. albicans biofilms to antifungals. We investigated the transcriptional profile of three genes (BGL2, SUN41, ECE1) involved in Candida cell wall formation in response to voriconazole or anidulafungin after the production of intermediate and mature biofilms. C. albicans M61, a well-documented biofilm producer strain, was used for the development of intermediate (12 h and 18 h) and completely mature biofilms (48 h). After exposure of cells from each biofilm growth mode to voriconazole (128 and 512 mg l(-1)) or anidulafungin (0.25 and 1 mg l(-1)) for 12-24 h, total RNA samples extracted from biofilm cells were analysed by RT-PCR. The voriconazole and anidulafungin biofilm MIC was 512 and 0.5 mg l(-1) respectively. Anidulafungin caused significant up-regulation of SUN41 (3.7-9.3-fold) and BGL2 (2.2-2.8 fold) in intermediately mature biofilms; whereas, voriconazole increased gene expression in completely mature biofilms (SUN41 2.3-fold, BGL2 2.1-fold). Gene expression was primarily down-regulated by voriconazole in intermediately, but not completely mature biofilms. Both antifungals caused down-regulation of ECE1 in intermediately mature biofilms.

  11. Antifungal agents commonly used in the superficial and mucosal candidiasis treatment: mode of action and resistance development

    PubMed Central

    Bondaryk, Małgorzata; Kurzątkowski, Wiesław

    2013-01-01

    Recent progress in medical sciences and therapy resulted in an increased number of immunocompromised individuals. Candida albicans is the leading opportunistic fungal pathogen causing infections in humans, ranging from superficial mucosal lesions to disseminated or bloodstream candidiasis. Superficial candidiasis not always presents a risk to the life of the infected host, however it significantly lowers the quality of life. Superficial Candida infections are difficult to treat and their frequency of occurrence is currently rising. To implement successful treatment doctors should be up to date with better understanding of C. albicans resistance mechanisms. Despite high frequency of Candida infections there is a limited number of antimycotics available for therapy. This review focuses on current understanding of the mode of action and resistance mechanisms to conventional and emerging antifungal agents for treatment of superficial and mucosal candidiasis. PMID:24353489

  12. Targeting efflux pumps to overcome antifungal drug resistance.

    PubMed

    Holmes, Ann R; Cardno, Tony S; Strouse, J Jacob; Ivnitski-Steele, Irena; Keniya, Mikhail V; Lackovic, Kurt; Monk, Brian C; Sklar, Larry A; Cannon, Richard D

    2016-08-01

    Resistance to antifungal drugs is an increasingly significant clinical problem. The most common antifungal resistance encountered is efflux pump-mediated resistance of Candida species to azole drugs. One approach to overcome this resistance is to inhibit the pumps and chemosensitize resistant strains to azole drugs. Drug discovery targeting fungal efflux pumps could thus result in the development of azole-enhancing combination therapy. Heterologous expression of fungal efflux pumps in Saccharomyces cerevisiae provides a versatile system for screening for pump inhibitors. Fungal efflux pumps transport a range of xenobiotics including fluorescent compounds. This enables the use of fluorescence-based detection, as well as growth inhibition assays, in screens to discover compounds targeting efflux-mediated antifungal drug resistance. A variety of medium- and high-throughput screens have been used to identify a number of chemical entities that inhibit fungal efflux pumps.

  13. 3-Bromopyruvate: a novel antifungal agent against the human pathogen Cryptococcus neoformans.

    PubMed

    Dyląg, Mariusz; Lis, Paweł; Niedźwiecka, Katarzyna; Ko, Young H; Pedersen, Peter L; Goffeau, Andre; Ułaszewski, Stanisław

    2013-05-03

    We have investigated the antifungal activity of the pyruvic acid analogue: 3-bromopyruvate (3-BP). Growth inhibition by 3-BP of 110 strains of yeast-like and filamentous fungi was tested by standard spot tests or microdilution method. The human pathogen Cryptococcus neoformans exhibited a low Minimal Inhibitory Concentration (MIC) of 0.12-0.15 mM 3-BP. The high toxicity of 3-BP toward C. neoformans correlated with high intracellular accumulation of 3-BP and also with low levels of intracellular ATP and glutathione. Weak cytotoxicity towards mammalian cells and lack of resistance conferred by the PDR (Pleiotropic Drug Resistance) network in the yeast Saccharomyces cerevisiae, are other properties of 3-BP that makes it a novel promising anticryptococcal drug.

  14. Carboxymethylated chitosan-stabilized copper nanoparticles: a promise to contribute a potent antifungal and antibacterial agent

    NASA Astrophysics Data System (ADS)

    Tantubay, Sangeeta; Mukhopadhyay, Sourav K.; Kalita, Himani; Konar, Suraj; Dey, Satyahari; Pathak, Amita; Pramanik, Panchanan

    2015-06-01

    Carboxymethylated chitosan (CMC)-stabilized copper nanoparticles (Cu-NPs) have been synthesized via chemical reduction of copper(II)-CMC complex in aqueous medium by hydrazine under microwave irradiation in ambient atmosphere. Structural morphology, phase, and chemical compositions of CMC-stabilized Cu-NPs (CMC-Cu-NPs) have been analyzed through high-resolution transmission electron microscopy, field emission scanning electron microscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. Antifungal and antibacterial activities of CMC-Cu-NPs have been evaluated against Candida tropicalis and Escherichia coli through agar well diffusion method, broth microdilution assay, live-dead assay, and microscopic observation. Antimicrobial activity of spherical CMC-Cu-NPs ( 4-15 nm of diameters) has been observed to be significant for both C. tropicalis and E. coli. The cytotoxicity study indicates that CMC-Cu-NPs have no significant toxic effect against normal cell line, L929.

  15. Synthesis and Biological Evaluation of Benzimidazole Phenylhydrazone Derivatives as Antifungal Agents against Phytopathogenic Fungi.

    PubMed

    Wang, Xing; Chen, Yong-Fei; Yan, Wei; Cao, Ling-Ling; Ye, Yong-Hao

    2016-11-22

    A series of benzimidazole phenylhydrazone derivatives (6a-6ai) were synthesized and characterized by ¹H-NMR, ESI-MS, and elemental analysis. The structure of 6b was further confirmed by single crystal X-ray diffraction as (E)-configuration. All the compounds were screened for antifungal activity against Rhizoctonia solani and Magnaporthe oryzae employing a mycelium growth rate method. Compound 6f exhibited significant inhibitory activity against R. solani and M. oryzae with the EC50 values of 1.20 and 1.85 μg/mL, respectively. In vivo testing demonstrated that 6f could effectively control the development of rice sheath blight (RSB) and rice blast (RB) caused by the above two phytopathogens. This work indicated that the compound 6f with a benzimidazole phenylhydrazone scaffold could be considered as a leading structure for the development of novel fungicides.

  16. An in vitro study of antifungal drug susceptibility of Candida species isolated from human immunodeficiency virus seropositive and human immunodeficiency virus seronegative individuals in Lucknow population Uttar Pradesh

    PubMed Central

    Dar, Mohammad Shafi; Sreedar, Gadiputi; Shukla, Abhilasha; Gupta, Prashant; Rehan, Ahmad Danish; George, Jiji

    2015-01-01

    Background: Candidiasis is the most common opportunistic infection in human immunodeficiency virus (HIV) seropositive patients, starting from asymptomatic colonization to pathogenic forms and gradual colonization of non-albicans in patients with advanced immunosuppression leads to resistance for azole group of antifungal drugs with high rate of morbidity and mortality. Objectives: To isolate the Candida species and determine of antifungal drug susceptibility against fluconazole, itraconazole, nystatin, amphotericin B, and clotrimazolein HIV seropositive and control individuals, with or without clinical oropharyngeal candidiasis (OPC). Materials and Methods: Includes samples from faucial region of 70 subjects with and without clinical candidiasis in HIV seropositive and controls were aseptically inoculated onto Sabaraud's Dextrose Agar media and yeasts were identified for the specific species by Corn Meal Agar, sugar fermentation and heat tolerance tests. Antifungal drug susceptibility of the isolated species was done against above-mentioned drugs by E-test and disc diffusion method. Results: The commonly isolated species in HIV seropositive and controls were Candida albicans, Candida glabrata and Candida tropicalis Candida guilliermondii and Candida dubliniensis isolated only in HIV seropositive patients. Susceptibility against selected antifungal drugs was observed more in HIV-negative individuals whereas susceptible dose-dependent and resistance were predominant in HIV-positive patients. Conclusion: Resistance is the major problem in the therapy of OPC, especially in HIV seropositive patients due to aggressive and prolonged use of antifungal agents, therefore, our study emphasizes the need for antifungal drug susceptibility testing whenever antifungal treatment is desired, especially in HIV-infected subjects. PMID:26604498

  17. Azole-resistant Candida albicans from a wild Brazilian porcupine (Coendou prehensilis): a sign of an environmental imbalance?

    PubMed

    Castelo-Branco, D S C M; Brilhante, R S N; Paiva, M A N; Teixeira, C E C; Caetano, E P; Ribeiro, J F; Cordeiro, R A; Sidrim, J J C; Monteiro, A J; Rocha, M F G

    2013-07-01

    This study aimed at evaluating the in vitro antifungal susceptibility of Candida albicans isolates obtained during necropsy of a wild Brazilian porcupine and the mechanism of azole resistance. Initially, we investigated the in vitro susceptibility of the three isolates to amphotericin B, caspofungin, fluconazole, itraconazole, ketoconazole and voriconazole. Afterwards, three sub-inhibitory concentrations (47, 21 and 12 mg/l) of promethazine, an efflux pump inhibitor, were tested in combination with the antifungal drugs in order to evaluate the role of these pumps in the development of antifungal resistance. In addition, the three isolates were submitted to RAPD-PCR and M13-fingerprinting analyses. The minimum inhibitory concentrations (MICs) obtained with the isolates were 1, 0.03125, 250, 125, 8 and 250 mg/l for amphotericin B, caspofungin, fluconazole, itraconazole, ketoconazole and voriconazole, respectively, and the isolates were found to be resistant to all tested azoles. The addition of the three subinhibitory concentrations of promethazine resulted in statistically significant (P < 0.05) reductions in the MICs for all tested drugs, with decreases to azoles being statistically greater than those for amphotericin B and caspofungin (P < 0.05). The molecular analyses showed a genetic similarity among the three tested isolates, suggesting the occurrence of candidemia in the studied animal. These findings highlight the importance of monitoring antifungal susceptibility of Candida spp. from veterinary sources, especially as they may indicate the occurrence of primary azole resistance even in wild animals.

  18. Antifungal resistance in yeast vaginitis.

    PubMed Central

    Dun, E.

    1999-01-01

    The increased number of vaginal yeast infections in the past few years has been a disturbing trend, and the scientific community has been searching for its etiology. Several theories have been put forth to explain the apparent increase. First, the recent widespread availability of low-dosage, azole-based over-the-counter antifungal medications for vaginal yeast infections encourages women to self-diagnose and treat, and women may be misdiagnosing themselves. Their vaginitis may be caused by bacteria, parasites or may be a symptom of another underlying health condition. As a result, they may be unnecessarily and chronically expose themselves to antifungal medications and encourage fungal resistance. Second, medical technology has increased the life span of seriously immune compromised individuals, yet these individuals are frequently plagued by opportunistic fungal infections. Long-term and intense azole-based antifungal treatment has been linked to an increase in resistant Candida and non-Candida species. Thus, the future of limiting antifungal resistance lies in identifying the factors promoting resistance and implementing policies to prevent it. PMID:10907778

  19. Perillaldehyde, a Promising Antifungal Agent Used in Food Preservation, Triggers Apoptosis through a Metacaspase-Dependent Pathway in Aspergillus flavus.

    PubMed

    Tian, Jun; Wang, Yanzhen; Lu, Zhaoqun; Sun, Chunhui; Zhang, Man; Zhu, Aihua; Peng, Xue

    2016-10-05

    In the present study, we provide detailed insights into perillaldehyde (PAE)'s mechanisms of action on Aspergillus flavus and offer evidence in favor of the induction of an apoptosis-like phenotype. Specifically, PAE's antifungal mode of action was investigated through the detection of mitochondrial membrane potential (MtΔψ) and phosphatidylserine (PS) exposure, as well as intracellular Ca(2+) level, reactive oxygen species accumulation, and metacaspase activation. This was done by way of fluorometry, measuring DNA fragmentation, and condensation by fluorescent microscopy. Furthermore, we searched for phenotypic changes characteristic of apoptosis by transmission electron microscopy and flow cytometry, determining the amount of cytochrome c released using Western blotting. Results indicated that cultivation of A. flavus in the presence of PAE caused depolarization of MtΔψ, rapid DNA condensation, large-scale DNA fragmentation, and an elevation of intracellular Ca(2+) level. The percentage of early apoptotic cells with exposure of PS were 27.4% and 48.7%, respectively, after 9 h incubations with 0.25 and 0.5 μL/mL of PAE. The percentage of stained cells with activated intracellular metacaspases exposed to PAE at concentrations of 0.25 and 0.5 μL/mL compared with control subjects were increased by 28.4 ± 3.25% and 37.9 ± 4.24%, respectively. The above results has revealed that PAE induces fungal apoptosis through a caspase-dependent mitochondrial pathway. In all, our findings provide a novel mechanism for exploring a possible antifungal agent used in food preservation.

  20. Burkholderia terrae BS001 migrates proficiently with diverse fungal hosts through soil and provides protection from antifungal agents

    PubMed Central

    Nazir, Rashid; Tazetdinova, Diana I.; van Elsas, Jan Dirk

    2014-01-01

    Soil bacteria can benefit from co-occurring soil fungi in respect of the acquisition of carbonaceous nutrients released by fungal hyphae and the access to novel territories in soil. Here, we investigated the capacity of the mycosphere-isolated bacterium Burkholderia terrae BS001 to comigrate through soil along with hyphae of the soil fungi Trichoderma asperellum, Rhizoctonia solani, Fusarium oxysporum, F. oxysporum pv lini, Coniochaeta ligniaria, Phanerochaete velutina, and Phallus impudicus. We used Lyophyllum sp. strain Karsten as the reference migration-inciting fungus. Bacterial migration through presterilized soil on the extending fungal hyphae was detected with six of the seven test fungi, with only Phallus impudicus not showing any bacterial transport. Much like with Lyophyllum sp. strain Karsten, intermediate (106–108 CFU g-1 dry soil) to high (>108 CFU g-1 dry soil) strain BS001 cell population sizes were found at the hyphal migration fronts of four fungi, i.e., T. asperellum, Rhizoctonia solani, F. oxysporum and F. oxysporum pv lini, whereas for two fungi, Coniochaeta ligniaria and Phanerochaete velutina, the migration responses were retarded and population sizes were lower (103–106 CFU g-1 dry soil). Consistent with previous data obtained with the reference fungus, migration with the migration-inciting fungi occurred only in the direction of the hyphal growth front. Remarkably, Burkholderia terrae BS001 provided protection from several antifungal agents to the canonical host Lyophyllum sp. strain Karsten. Specifically, this host was protected from Pseudomonas fluorescens strain CHA0 metabolites, as well as from the anti-fungal agent cycloheximide. Similar protection by strain BS001was observed for T. asperellum, and, to a lower extent, F. oxysporum and Rhizoctonia solani. The protective effect may be related to the consistent occurrence of biofilm-like cell layers or agglomerates at the surfaces of the protected fungi. The current study represents

  1. Synthesis and Biological Evaluation of New Eugenol Mannich Bases as Promising Antifungal Agents.

    PubMed

    Abrão, Pedro Henrique O; Pizi, Rafael B; de Souza, Thiago B; Silva, Naiara C; Fregnan, Antonio M; Silva, Fernanda N; Coelho, Luiz Felipe L; Malaquias, Luiz Cosme C; Dias, Amanda Latercia T; Dias, Danielle F; Veloso, Marcia P; Carvalho, Diogo T

    2015-10-01

    New Mannich base-type eugenol derivatives were synthesized and evaluated for their anticandidal activity using a broth microdilution assay. Among the synthesized compounds, 4-allyl-2-methoxy-6-(morpholin-4-ylmethyl) phenyl benzoate (7) and 4-{5-allyl-2-[(4-chlorobenzoyl)oxy]-3-methoxybenzyl}morpholin-4-ium chloride (8) were found to be the most effective antifungal compounds with low IC50 values, some of them well below those of reference drug fluconazole. The most significant IC50 values were those of 7 against C. glabrata (1.23 μm), C. albicans and C. krusei (both 0.63 μm). Additionally, the synthesized compounds were evaluated for their in vitro cytotoxic effects on human mononuclear cells. As result, the cytotoxic activity of eugenol in eukaryotic cells decreased with the introduction of the morpholinyl group. Given these findings, we point out compounds 7 and 8 as the most promising derivatives because they showed potency values greater than those of eugenol and fluconazole and they also presented high selectivity indexes.

  2. Identification and evaluation of novel acetolactate synthase inhibitors as antifungal agents.

    PubMed

    Richie, Daryl L; Thompson, Katherine V; Studer, Christian; Prindle, Vivian C; Aust, Thomas; Riedl, Ralph; Estoppey, David; Tao, Jianshi; Sexton, Jessica A; Zabawa, Thomas; Drumm, Joseph; Cotesta, Simona; Eichenberger, Jürg; Schuierer, Sven; Hartmann, Nicole; Movva, N Rao; Tallarico, John A; Ryder, Neil S; Hoepfner, Dominic

    2013-05-01

    High-throughput phenotypic screening against the yeast Saccharomyces cerevisiae revealed a series of triazolopyrimidine-sulfonamide compounds with broad-spectrum antifungal activity, no significant cytotoxicity, and low protein binding. To elucidate the target of this series, we have applied a chemogenomic profiling approach using the S. cerevisiae deletion collection. All compounds of the series yielded highly similar profiles that suggested acetolactate synthase (Ilv2p, which catalyzes the first common step in branched-chain amino acid biosynthesis) as a possible target. The high correlation with profiles of known Ilv2p inhibitors like chlorimuron-ethyl provided further evidence for a similar mechanism of action. Genome-wide mutagenesis in S. cerevisiae identified 13 resistant clones with 3 different mutations in the catalytic subunit of acetolactate synthase that also conferred cross-resistance to established Ilv2p inhibitors. Mapping of the mutations into the published Ilv2p crystal structure outlined the chlorimuron-ethyl binding cavity, and it was possible to dock the triazolopyrimidine-sulfonamide compound into this pocket in silico. However, fungal growth inhibition could be bypassed through supplementation with exogenous branched-chain amino acids or by the addition of serum to the medium in all of the fungal organisms tested except for Aspergillus fumigatus. Thus, these data support the identification of the triazolopyrimidine-sulfonamide compounds as inhibitors of acetolactate synthase but suggest that targeting may be compromised due to the possibility of nutrient bypass in vivo.

  3. High-performance liquid chromatographic analysis of new triazole antifungal agent SYN-2869 and its derivatives in plasma.

    PubMed

    Khan, J K; Montaseri, H; Poglod, M; Bu, H Z; Daneshtalab, M; Micetich, R G

    1999-09-01

    A simple reversed-phase high-performance liquid chromatography (HPLC) method with UV detection was developed and validated for the quantitation of SYN-2869, a novel triazole antifungal agent and its analogs in rat plasma. The method involved a simple precipitation of plasma protein with acetonitrile (1:10 ratio). The reconstituted sample after evaporation to dryness was injected onto a HPLC column. SYN-2869 and its analogs were separated from the matrix components on a symmetry C18 column using an aqueous mobile phase of acetonitrile and water with a flow rate of 1 ml min(-1). A step gradient of 40-80% acetonitrile eluted all four compounds. The run time was 30 min. The linear range was 0.5 10 microg ml(-1)(r2 > 0.999). The limit of quantitation was 0.5 microg ml(-1). The inter-day precision and accuracy for SYN-2869 standard concentration were from 1.9 to 8.5% and from 1.4 to +/- 4.40%, respectively. The precision and accuracy of intra-day quality control samples were from 4.6 to 5.2% and from 4.6 to 12%, respectively.

  4. The AUR1 gene in Saccharomyces cerevisiae encodes dominant resistance to the antifungal agent aureobasidin A (LY295337).

    PubMed Central

    Heidler, S A; Radding, J A

    1995-01-01

    Aureobasidin A (LY295337) is a cyclic depsipeptide antifungal agent with activity against Candida spp. The mechanism of action of LY295337 remains unknown. LY295337 also shows activity against the yeast Saccharomyces cerevisiae. Generation of a mutant of S. cerevisiae resistant to LY295337 is reported. Resistance was found to reside in a dominant mutation of a single gene which has been named AUR1 (aureobasidin resistance). This gene was cloned and sequenced. A search for homologous sequences in GenBank and by BLAST did not elucidate the function of this gene, although sequence homology too an open reading frame from the Saccharomyces genome sequencing project and several other adjacent loci was noted. Deletion of aur1 was accomplished in a diploid S. cerevisiae strain. Subsequent sporulation and dissection of the aur1/aur1 delta diploid resulted in tetrads demonstrating 2:2 segregation of viable and nonviable spores, indicating that deletion of aur1 is lethal. As LY295337 is fungicidal and deletion of aur1 is lethal, aur1 represents a potential candidate for the target of LY295337. PMID:8593016

  5. Identification, antifungal susceptibility and scanning electron microscopy of a keratinolytic strain of Rhodotorula mucilaginosa: a primary causative agent of onychomycosis.

    PubMed

    da Cunha, Marcel M L; dos Santos, Luana P B; Dornelas-Ribeiro, Marcos; Vermelho, Alane B; Rozental, Sonia

    2009-04-01

    Onychomycosis is a dermatological problem of high prevalence that mainly affects the hallux toenail. Onychomycosis caused by the yeast Rhodotorula mucilaginosa was identified using colony morphology, light microscopy, urease and carbohydrate metabolism in a 57-year-old immunocompetent patient from Rio de Janeiro, Brazil. High-resolution scanning electron microscopy of nail fragments, processed by a noncoating method, led to the observation with fine detail of the structures of both nail and fungus involved in the infection. Yeasts were mainly found inside grooves in the nail. Budding yeasts presented a spiral pattern of growth and blastoconidia were found in the nail groove region. Keratinase assays and keratin enzymography revealed that this isolate was highly capable of degrading keratin. Antifungal susceptibility tests showed that the fungus was susceptible to low concentrations of amphotericin B and 5-flucytosine and resistant to high concentrations of fluconazole, itraconazole, voriconazole and terbinafine. These findings showed data for the first time concerning the interaction of R. mucilaginosa in toenail infection and suggest that this emerging yeast should also be considered an opportunistic primary causative agent of onychomycosis.

  6. Antifungal polypeptides

    DOEpatents

    Altier, Daniel J.; Ellanskaya, Irina; Ellanskaya, legal representative, Natalia; Gilliam, Jacob T.; Hunter-Cevera, Jennie; Presnail, James K.; Schepers, Eric; Simmons, Carl R.; Torok, Tamas; Yalpani, Nasser

    2009-09-15

    The invention relates to antifungal compositions and methods for protecting a plant from a fungal pathogen. Compositions including antifungal polypeptides isolated from a fungal fermentation broth are provided.

  7. Search for antibacterial and antifungal agents from selected Indian medicinal plants.

    PubMed

    Kumar, V Prashanth; Chauhan, Neelam S; Padh, Harish; Rajani, M

    2006-09-19

    A series of 61 Indian medicinal plants belonging to 33 different families used in various infectious disorders, were screened for their antimicrobial properties. Screening was carried out at 1000 and 500 microg/ml concentrations by agar dilution method against Bacillus cereus var mycoides, Bacillus pumilus, Bacillus subtilis, Bordetella bronchiseptica, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Streptococcus faecalis, Candida albicans, Aspergillus niger and Saccharomyces cerevisiae. Twenty-eight plant extracts showed activity against at least one of the test organisms used in the screening. On the basis of the results obtained, we conclude that the crude extracts of Dorema ammoniacum, Sphaeranthus indicus, Dracaena cinnabari, Mallotus philippinensis, Jatropha gossypifolia, Aristolochia indica, Lantana camara, Nardostachys jatamansi, Randia dumetorum and Cassia fistula exhibited significant antimicrobial activity and properties that support folkloric use in the treatment of some diseases as broad-spectrum antimicrobial agents. This probably explains the use of these plants by the indigenous people against a number of infections.

  8. Management of symptomatic erosive-ulcerative lesions of oral lichen planus in an adult Egyptian population using Selenium-ACE combined with topical corticosteroids plus antifungal agent

    PubMed Central

    Belal, Mahmoud Helmy

    2015-01-01

    Aim: Oral lichen planus (OLP) is a chronic mucocutaneous disease with an immunological etiology. This study was conducted to evaluate the effect of selenium combined with Vitamins A, C & E (Selenium-ACE) in the treatment of erosive-ulcerative OLP as an adjunctive to topical corticosteroids plus antifungal agent. Subjects and Methods: Thirty patients with a confirmed clinical and histopathologic diagnosis of OLP participated in this clinical trial. Patients were randomly allocated into one of three groups and treated as follows: (I) Topical corticosteroids, (II) topical corticosteroids plus antifungal, and (III) SE-ACE combined with topical corticosteroids plus antifungal. The patients were followed for 6 weeks. The pain and severity of the lesions were recorded at the initial and follow-up visits. All recorded data were analyzed using paired t-test and ANOVA test. A P ≤ 0.05 was considered significant. Results: The experimental groups showed a marked reduction in pain sensation and size of lesions, particularly in the final follow-up period, but there was no significant difference between the first two Groups I and II. However, healing of lesions and improvement of pain sensation was effective in Group III since a significant difference was found favoring Group III over both Groups I and II. Conclusion: No significant difference was found in treating erosive-ulcerative lesions of OLP by topical corticosteroids alone or combined with antifungal. However, when using SE-ACE in combination with topical corticosteroids plus antifungal, this approach may be effective in managing ulcerative lesions of OLP; but more research with a larger sample size and a longer evaluation period may be recommended. PMID:26681847

  9. Novel macrocyclic molecules based on 12a-N substituted 16-membered azalides and azalactams as potential antifungal agents.

    PubMed

    Wang, Xiaolei; Zhang, Shun; Pang, Yanlong; Yuan, Huihui; Liang, Xiaomei; Zhang, Jianjun; Wang, Daoquan; Wang, Mingan; Dong, Yanhong

    2014-02-12

    Novel macrocyclic molecules comprising sulfonyl and acyl moiety at the position N-12a of 16-membered azalides (6a-n) and azalactams (10a-r) scaffold were synthesized from cyclododecanone 1 as starting material via 5 steps and 4 steps, respectively. The antifungal activity of these compounds against Sclerotinia sclerotiorum, Pyricularia oryzae, Botrytis cinerea, Rhizoctonia solani and Phytophthora capsici were evaluated and found that compounds possessing α-exomethylene (6c, 6d, 6e and 6g) showed antifungal activity comparable to commercial fungicide Chlorothalonil against P. oryzae and compounds possessing p-chlorobenzoyl exhibited enhanced antifungal activity than those with other substituents against S. sclerotiorum, P. oryzae, and B. cinerea. These findings suggested that the α-exomethylene and p-chlorobenzoyl may be two potential pharmacological active groups with antifungal activities.

  10. Combination Effects of (Tri)Azole Fungicides on Hormone Production and Xenobiotic Metabolism in a Human Placental Cell Line

    PubMed Central

    Rieke, Svenja; Koehn, Sophie; Hirsch-Ernst, Karen; Pfeil, Rudolf; Kneuer, Carsten; Marx-Stoelting, Philip

    2014-01-01

    Consumers are exposed to multiple residues of different pesticides via the diet. Therefore, EU legislation for pesticides requires the evaluation of single active substances as well as the consideration of combination effects. Hence the analysis of combined effects of substances in a broad dose range represents a key challenge to current experimental and regulatory toxicology. Here we report evidence for additive effects for (tri)azole fungicides, a widely used group of antifungal agents, in the human placental cell line Jeg-3. In addition to the triazoles cyproconazole, epoxiconazole, flusilazole and tebuconazole and the azole fungicide prochloraz also pesticides from other chemical classes assumed to act via different modes of action (i.e., the organophosphate chlorpyrifos and the triazinylsulfonylurea herbicide triflusulfuron-methyl) were investigated. Endpoints analysed include synthesis of steroid hormone production (progesterone and estradiol) and gene expression of steroidogenic and non-steroidogenic cytochrome-P-450 (CYP) enzymes. For the triazoles and prochloraz, a dose dependent inhibition of progesterone production was observed and additive effects could be confirmed for several combinations of these substances in vitro. The non-triazoles chlorpyrifos and triflusulfuron-methyl did not affect this endpoint and, in line with this finding, no additivity was observed when these substances were applied in mixtures with prochloraz. While prochloraz slightly increased aromatase expression and estradiol production and triflusulfuron-methyl decreased estradiol production, none of the other substances had effects on the expression levels of steroidogenic CYP-enzymes in Jeg-3 cells. For some triazoles, prochloraz and chlorpyrifos a significant induction of CYP1A1 mRNA expression and potential combination effects for this endpoint were observed. Inhibition of CYP1A1 mRNA induction by the AhR inhibitor CH223191 indicated AhR receptor dependence of this effect. PMID

  11. Combination effects of (tri)azole fungicides on hormone production and xenobiotic metabolism in a human placental cell line.

    PubMed

    Rieke, Svenja; Koehn, Sophie; Hirsch-Ernst, Karen; Pfeil, Rudolf; Kneuer, Carsten; Marx-Stoelting, Philip

    2014-09-17

    Consumers are exposed to multiple residues of different pesticides via the diet. Therefore, EU legislation for pesticides requires the evaluation of single active substances as well as the consideration of combination effects. Hence the analysis of combined effects of substances in a broad dose range represents a key challenge to current experimental and regulatory toxicology. Here we report evidence for additive effects for (tri)azole fungicides, a widely used group of antifungal agents, in the human placental cell line Jeg-3. In addition to the triazoles cyproconazole, epoxiconazole, flusilazole and tebuconazole and the azole fungicide prochloraz also pesticides from other chemical classes assumed to act via different modes of action (i.e., the organophosphate chlorpyrifos and the triazinylsulfonylurea herbicide triflusulfuron-methyl) were investigated. Endpoints analysed include synthesis of steroid hormone production (progesterone and estradiol) and gene expression of steroidogenic and non-steroidogenic cytochrome-P-450 (CYP) enzymes. For the triazoles and prochloraz, a dose dependent inhibition of progesterone production was observed and additive effects could be confirmed for several combinations of these substances in vitro. The non-triazoles chlorpyrifos and triflusulfuron-methyl did not affect this endpoint and, in line with this finding, no additivity was observed when these substances were applied in mixtures with prochloraz. While prochloraz slightly increased aromatase expression and estradiol production and triflusulfuron-methyl decreased estradiol production, none of the other substances had effects on the expression levels of steroidogenic CYP-enzymes in Jeg-3 cells. For some triazoles, prochloraz and chlorpyrifos a significant induction of CYP1A1 mRNA expression and potential combination effects for this endpoint were observed. Inhibition of CYP1A1 mRNA induction by the AhR inhibitor CH223191 indicated AhR receptor dependence this effect.

  12. Discontinuation of echinocandin and azole treatments led to the disappearance of an FKS alteration but not azole resistance during clonal Candida glabrata persistent candidaemia.

    PubMed

    Imbert, S; Castain, L; Pons, A; Jacob, S; Meyer, I; Palous, M; Vezinet, C; Langeron, O; Hennequin, C; Monsel, A; Fekkar, A

    2016-10-01

    To give an indication of a fitness cost conferred by FKS mutation-associated echinocandin resistance in Candida glabrata during human infection. Six C. glabrata clinical strains sequentially isolated from blood and a hepatic abscess in a solid organ transplant recipient were analysed. The patient had received long-term azole and echinocandin therapy for invasive aspergillosis and persistent candidaemia. Minimal inhibitory concentrations were determined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution method. Molecular mechanisms of antifungal resistance were determined by sequencing hot spots of the FKS. Strain relatedness was determined using a microsatellite-based typing method. Typing analysis revealed an identical microsatellite pattern for all isolates, supporting a close relation. The first C. glabrata isolate showed wild-type phenotype (i.e. susceptibility to echinocandins and low level of azole resistance). After voriconazole therapy, the C. glabrata quickly acquired pan-azole resistance. Later, echinocandin treatment led to the emergence of a FKS2 S663P alteration and echinocandin resistance. After disruption of both azole and echinocandin therapy in favour of liposomal amphotericin B, C. glabrata isolates regained full susceptibility to echinocandin and lost the FKS2 S663P alteration while nonetheless maintaining their pan-azole resistance. Our clinical report supports the potential existence of a fitness cost conferred by FKS mutation in C. glabrata, as disruption of treatment led to a rapid disappearance of the resistant clone. This suggests that a more restricted use and/or a discontinuous administration of echinocandins may limit the spread of clinical resistance to this class.

  13. The in vitro antifungal activity of sudanese medicinal plants against Madurella mycetomatis, the eumycetoma major causative agent.

    PubMed

    Elfadil, Hassabelrasoul; Fahal, Ahmed; Kloezen, Wendy; Ahmed, Elhadi M; van de Sande, Wendy

    2015-03-01

    Eumycetoma is a debilitating chronic inflammatory fungal infection that exists worldwide but it is endemic in many tropical and subtropical regions. The major causative organism is the fungus Madurella mycetomatis. The current treatment of eumycetoma is suboptimal and characterized by low cure rate and high recurrence rates. Hence, an alternative therapy is needed to address this. Here we determined the antifungal activity of seven Sudanese medicinal plant species against Madurella mycetomatis. Of these, only three species; Boswellia papyrifera, Acacia nubica and Nigella sativa, showed some antifungal activity against M. mycetomatis and were further studied. Crude methanol, hexane and defatted methanol extracts of these species were tested for their antifungal activity. B. papyrifera had the highest antifungal activity (MIC50 of 1 ug/ml) and it was further fractionated. The crude methanol and the soluble ethyl acetate fractions of B. papyrifera showed some antifungal activity. The Gas-Liquid-Chromatography hybrid Mass-Spectrophotometer analysis of these two fractions showed the existence of beta-amyrin, beta-amyrone, beta-Sitosterol and stigmatriene. Stigmatriene had the best antifungal activity, compared to other three phytoconstituents, with an MIC-50 of 32 μg/ml. Although the antifungal activity of the identified phytoconstituents was only limited, the antifungal activity of the complete extracts is more promising, indicating synergism. Furthermore these plant extracts are also known to have anti-inflammatory activity and can stimulate wound-healing; characteristics which might also be of great value in the development of novel therapeutic drugs for this chronic inflammatory disease. Therefore further exploration of these plant species in the treatment of mycetoma is encouraging.

  14. Functional expression of P-glycoprotein in Saccharomyces cerevisiae confers cellular resistance to the immunosuppressive and antifungal agent FK520.

    PubMed Central

    Raymond, M; Ruetz, S; Thomas, D Y; Gros, P

    1994-01-01

    We have recently reported that expression in yeast cells of P-glycoprotein (P-gp) encoded by the mouse multidrug resistance mdr3 gene (Mdr3) can complement a null ste6 mutation (M. Raymond, P. Gros, M. Whiteway, and D. Y. Thomas, Science 256:232-234, 1992). Here we show that Mdr3 behaves as a fully functional drug transporter in this heterologous expression system. Photolabelling experiments indicate that Mdr3 synthesized in yeast cells binds the drug analog [125I]iodoaryl azidoprazosin, this binding being competed for by vinblastine and tetraphenylphosphonium bromide, two known multidrug resistance drugs. Spheroplasts expressing wild-type Mdr3 (Ser-939) exhibit an ATP-dependent and verapamil-sensitive decreased accumulation of [3H]vinblastine as compared with spheroplasts expressing a mutant form of Mdr3 with impaired transport activity (Phe-939). Expression of Mdr3 in yeast cells can confer resistance to growth inhibition by the antifungal and immunosuppressive agent FK520, suggesting that this compound is a substrate for P-gp in yeast cells. Replacement of Ser-939 in Mdr3 by a series of amino acid substitutions is shown to modulate both the level of cellular resistance to FK520 and the mating efficiency of yeast mdr3 transformants. The effects of these mutations on the function of Mdr3 in yeast cells are similar to those observed in mammalian cells with respect to drug resistance and transport, indicating that transport of a-factor and FK520 in yeast cells is mechanistically similar to drug transport in mammalian cells. The ability of P-gp to confer cellular resistance to FK520 in yeast cells establishes a dominant phenotype that can be assayed for the positive selection of intragenic revertants of P-gp inactive mutants, an important tool for the structure-function analysis of mammalian P-gp in yeast cells. Images PMID:7505392

  15. Antifungal agents. Part 4: Synthesis and antifungal activities of novel indole[1,2-c]-1,2,4-benzotriazine derivatives against phytopathogenic fungi in vitro.

    PubMed

    Xu, Hui; Fan, Ling-Ling

    2011-01-01

    A series of novel indole[1,2-c]-1,2,4-benzotriazine derivatives were obtained by a modified Sandmeyer reaction in the presence of tert-butylnitrite (t-BuONO). As compared with hymexazol, a commercially available agricultural fungicide, at the concentration of 50 μg/mL, two indole[1,2-c]-1,2,4-benzotriazines, 5h and 5k, exhibited the more promising and pronounced antifungal activities in vitro against five phytopathogenic fungi. It clearly demonstrated that introduction of appropriate substituents on the indolyl ring of indole[1,2-c]-1,2,4-benzotriazine (5a) would lead to the more potent derivatives.

  16. In vivo activity of Sapindus saponaria against azole-susceptible and -resistant human vaginal Candida species

    PubMed Central

    2011-01-01

    Background Study of in vivo antifungal activity of the hydroalcoholic extract (HE) and n-BuOH extract (BUTE) of Sapindus saponaria against azole-susceptible and -resistant human vaginal Candida spp. Methods The in vitro antifungal activity of HE, BUTE, fluconazole (FLU), and itraconazole (ITRA) was determined by the broth microdilution method. We obtained values of minimal inhibitory concentration (MIC) and minimum fungicide concentration (MFC) for 46 strains of C. albicans and 10 of C. glabrata isolated from patients with vulvovaginal candidiasis (VVC). VVC was induced in hyperestrogenic Wistar rats with azole-susceptible C. albicans (SCA), azole-resistant C. albicans (RCA), and azole-resistant C. glabrata (RCG). The rats were treated intravaginally with 0.1 mL of HE or BUTE at concentrations of 1%, 2.5% and 5%; 100 μg/mL of FLU (treatment positive control); or distilled water (negative control) at 1, 24, and 48 h after induction of the infection, and the progress of VVC was monitored by culturing and scanning electron microscopy (SEM). The toxicity was evaluated in cervical cells of the HeLa cell line. Results The extracts showed in vitro inhibitory and fungicidal activity against all the isolates, and the MIC and MFC values for the C. glabrata isolates were slightly higher. In vivo, the SCA, RCA, and RCG infections were eliminated by 21 days post-infection, with up to 5% HE and BUTE, comparable to the activity of FLU. No cytotoxic action was observed for either extract. Conclusions Our results demonstrated that HE and BUTE from S. saponaria show inhibitory and fungicidal activity in vitro, in addition to in vivo activity against azole-resistant vaginal isolates of C. glabrata and azole-susceptible and resistant isolates of C. albicans. Also considering the lack of cytotoxicity and the low concentrations of the extracts necessary to eliminate the infection in vivo, HE and BUTE show promise for continued studies with purified antifungal substances in VVC yeast

  17. In vitro susceptibility patterns of clinically important Trichophyton and Epidermophyton species against nine antifungal drugs.

    PubMed

    Badali, Hamid; Mohammadi, Rasoul; Mashedi, Olga; de Hoog, G Sybren; Meis, Jacques F

    2015-05-01

    Despite the common, worldwide, occurrence of dermatophytes, little information is available regarding susceptibility profiles against currently available and novel antifungal agents. A collection of sixty-eight clinical Trichophyton species and Epidermophyton floccosum were previously identified and verified to the species level by sequencing the internal transcribed spacer (ITS) regions of rDNA. MICs of amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole, terbinafine and MECs of caspofungin and anidulafungin were performed based on CLSI M38-A2. The resulting MIC90 s of all strains were, in increasing order, as follows: terbinafine (0.063 mg l(-1) ); posaconazole (1 mg l(-1) ); isavuconazole and anidulafungin (2 mg l(-1) ); itraconazole, voriconazole, amphotericin B, and caspofungin (4 mg l(-1) ) and fluconazole (>64 mg l(-1) ). These results confirm that terbinafine is an excellent agent for treatment of dermatophytosis due to T. rubrum, T. mentagrophytes, T. verrucosum, T. schoenleinii and E. floccosum. In addition, the new azoles POS and ISA are potentially useful antifungals to treat dermatophytosis. However, the clinical effectiveness of these novel antifungals remains to be determined.

  18. Human mycoses and advances in antifungal therapy.

    PubMed

    Fromtling, R A

    2001-04-01

    The 11th Focus on Fungal Infections meeting was held in Washington, D.C., U.S.A., March 1416, 2001. At the conference, there were well-attended sessions that focused on the pathogenesis and therapy of fungal disease. This report focuses on new information on fungal incidence and pathogenesis as well as on the in vitro and clinical experience of established antifungal drugs (fluconazole, itraconazole, amphotericin B, liposomal formulations of amphotericin B, terbinafine) and the newer antifungal compounds approved for use (e.g., caspofungin) and in development (the new-generation azoles: voriconazole, posaconazole, ravuconazole, and the candins, micafungin and anidulafungin).

  19. Epidemiology, species distribution, antifungal susceptibility, and ERG11 mutations of Candida species isolated from pregnant Chinese Han women.

    PubMed

    Yang, L; Su, M Q; Ma, Y Y; Xin, Y J; Han, R B; Zhang, R; Wen, J; Hao, X K

    2016-04-28

    The widespread use of antifungal agents has led to increasing azole resistance in Candida species. A major azole-resistance mechanism involves point mutations in the ERG11 gene, which encodes cytochrome P450 lanosterol 14a-demethylase. In this study, vaginal swabs were obtained from 657 pregnant Chinese Han women and cultured appropriately. The open reading frame of the obtained fungal species were amplified by PCR and sequenced; additionally, the ERG11 gene of the isolated Candida species was amplified and sequenced, and the antifungal susceptibility of the isolated species was determined. The vaginal swabs of 124 women produced fungal cultures; five species of Candida were isolated from the patients, among which Candida albicans was predominant. Twelve C. albicans isolates (13.8%) were resistant to fluconazole and 2 (2.2%) were resistant to itraconazole. Seventeen mutations, including 9 silent and 8 missense mutations, were identified in the ERG11 gene of 31 C. albicans isolates. Our findings suggest that infection caused by C. albicans and non-C. albicansis common in Chinese Han women of reproductive age. Moreover, the relationship between Candida infection and certain epidemiological factors emphasizes the need to educate women about the precise diagnosis and punctual treatment of vaginitis.

  20. Efficacy of FK463, a New Lipopeptide Antifungal Agent, in Mouse Models of Disseminated Candidiasis and Aspergillosis

    PubMed Central

    Ikeda, Fumiaki; Wakai, Yoshimi; Matsumoto, Satoru; Maki, Katsuyuki; Watabe, Etsuko; Tawara, Shuichi; Goto, Toshio; Watanabe, Yuji; Matsumoto, Fumio; Kuwahara, Shogo

    2000-01-01

    The efficacy of intravenous injection of FK463, a novel water-soluble lipopeptide, was evaluated in mouse models of disseminated candidiasis and aspergillosis and was compared with those of fluconazole (FLCZ) and amphotericin B (AMPH-B). In the candidiasis model, FK463 significantly prolonged the survival of intravenously infected mice at doses of 0.125 mg/kg of body weight or higher. In disseminated candidiasis caused by Candida species, including FLCZ-resistant Candida albicans, FK463 exhibited an efficacy 1.4 to 18 times inferior to that of AMPH-B, with 50% effective doses (ED50s) ranging from 0.21 to 1.00 mg/kg and 0.06 to 0.26 mg/kg, respectively, and was much more active than FLCZ. The protective effect of FK463 was not obviously influenced by the fungal inoculum size, the starting time of the treatment, or the immunosuppressed status of the host. The reduction in efficacy was less than that observed with FLCZ or AMPH-B. The efficacy of FK463 was also evaluated in the disseminated candidiasis target organ assay and was compared with those of FLCZ and AMPH-B. Efficacies were evaluated on the basis of a comparison between the mean log10 CFU in kidneys in the groups treated with antifungal agents and that in control group. A single dose of FK463 at 0.5 mg/kg or higher significantly reduced the viable counts in kidneys compared with the numbers of yeast cells before treatment, and its efficacy was comparable to that of AMPH-B, while FLCZ at 4 mg/kg showed only a suppressive effect on the growth of C. albicans in the kidneys. In the disseminated aspergillosis model, FK463 given at doses of 0.5 mg/kg or higher significantly prolonged the survival of mice infected intravenously with Aspergillus fumigatus conidia. The efficacy of FK463 was about 2 times inferior to that of AMPH-B, with ED50s ranging from 0.25 to 0.50 mg/kg and 0.11 to 0.29 mg/kg, respectively. These results indicate that FK463 may be a potent parenterally administered therapeutic agent for

  1. Aspergillus fumigatus in the cystic fibrosis lung: pros and cons of azole therapy.

    PubMed

    Burgel, Pierre-Régis; Paugam, André; Hubert, Dominique; Martin, Clémence

    2016-01-01

    Aspergillus fumigatus is the main fungus cultured in the airways of patients with cystic fibrosis (CF). Allergic bronchopulmonary aspergillosis occurs in ~10% of CF patients and is clearly associated with airway damage and lung function decline. The effects of A. fumigatus colonization in the absence of allergic bronchopulmonary aspergillosis are less well established. Retrospective clinical studies found associations of A. fumigatus-positive cultures with computed tomography scan abnormalities, greater risk of CF exacerbations and hospitalizations, and/or lung function decline. These findings were somewhat variable among studies and provided only circumstantial evidence for a role of A. fumigatus colonization in CF lung disease progression. The availability of a growing number of oral antifungal triazole drugs, together with the results of nonrandomized case series suggesting positive effects of azole therapies, makes it tempting to treat CF patients with these antifungal drugs. However, the only randomized controlled trial that has used itraconazole in CF patients showed no significant benefit. Because triazoles may have significant adverse effects and drug interactions, and because their prolonged use has been associated with the emergence of azole-resistant A. fumigatus isolates, it remains unclear whether or not CF patients benefit from azole therapy.

  2. Aspergillus fumigatus in the cystic fibrosis lung: pros and cons of azole therapy

    PubMed Central

    Burgel, Pierre-Régis; Paugam, André; Hubert, Dominique; Martin, Clémence

    2016-01-01

    Aspergillus fumigatus is the main fungus cultured in the airways of patients with cystic fibrosis (CF). Allergic bronchopulmonary aspergillosis occurs in ~10% of CF patients and is clearly associated with airway damage and lung function decline. The effects of A. fumigatus colonization in the absence of allergic bronchopulmonary aspergillosis are less well established. Retrospective clinical studies found associations of A. fumigatus-positive cultures with computed tomography scan abnormalities, greater risk of CF exacerbations and hospitalizations, and/or lung function decline. These findings were somewhat variable among studies and provided only circumstantial evidence for a role of A. fumigatus colonization in CF lung disease progression. The availability of a growing number of oral antifungal triazole drugs, together with the results of nonrandomized case series suggesting positive effects of azole therapies, makes it tempting to treat CF patients with these antifungal drugs. However, the only randomized controlled trial that has used itraconazole in CF patients showed no significant benefit. Because triazoles may have significant adverse effects and drug interactions, and because their prolonged use has been associated with the emergence of azole-resistant A. fumigatus isolates, it remains unclear whether or not CF patients benefit from azole therapy. PMID:27703383

  3. Synergistic anticandidal activity of pure polyphenol curcumin I in combination with azoles and polyenes generates reactive oxygen species leading to apoptosis.

    PubMed

    Sharma, Monika; Manoharlal, Raman; Negi, Arvind Singh; Prasad, Rajendra

    2010-08-01

    We have shown previously that pure polyphenol curcumin I (CUR-I) shows antifungal activity against Candida species. By employing the chequerboard method, filter disc and time-kill assays, in the present study we demonstrate that CUR-I at non-antifungal concentration interacts synergistically with azoles and polyenes. For this, pure polyphenol CUR-I was tested for synergy with five azole and two polyene drugs - fluconazole (FLC), miconazole, ketoconazole (KTC), itraconazole (ITR), voriconazole (VRC), nystatin (NYS) and amphotericin B (AMB) - against 21 clinical isolates of Candida albicans with reduced antifungal sensitivity, as well as a drug-sensitive laboratory strain. Notably, there was a 10-35-fold drop in the MIC(80) values of the drugs when CUR-I was used in combination with azoles and polyenes, with fractional inhibitory concentration index (FICI) values ranging between 0.09 and 0.5. Interestingly, the synergistic effect of CUR-I with FLC and AMB was associated with the accumulation of reactive oxygen species, which could be reversed by the addition of an antioxidant such as ascorbic acid. Furthermore, the combination of CUR-I and FLC/AMB triggered apoptosis that could also be reversed by ascorbic acid. We provide the first evidence that pure CUR-I in combination with azoles and polyenes represents a novel therapeutic strategy to improve the activity of common antifungals.

  4. Inhibitors of the Glyoxylate Cycle Enzyme ICL1 in Candida albicans for Potential Use as Antifungal Agents

    PubMed Central

    Cheah, Hong-Leong; Lim, Vuanghao; Sandai, Doblin

    2014-01-01

    Candida albicans is an opportunistic pathogen that causes candidiasis in humans. In recent years, metabolic pathways in C. albicans have been explored as potential antifungal targets to treat candidiasis. The glyoxylate cycle, which enables C. albicans to survive in nutrient-limited host niches and its. Key enzymes (e.g., isocitrate lyase (ICL1), are particularly attractive antifungal targets for C. albicans. In this study, we used a new screening approach that better reflects the physiological environment that C. albicans cells experience during infection to identify potential inhibitors of ICL. Three compounds (caffeic acid (CAFF), rosmarinic acid (ROS), and apigenin (API)) were found to have antifungal activity against C. albicans when tested under glucose-depleted conditions. We further confirmed the inhibitory potential of these compounds against ICL using the ICL enzyme assay. Lastly, we assessed the bioavailability and toxicity of these compounds using Lipinski's rule-of-five and ADMET analysis. PMID:24781056

  5. Molecular structures and biological evaluation of 2-chloro-3-(n-alkylamino)-1,4-napthoquinone derivatives as potent antifungal agents

    NASA Astrophysics Data System (ADS)

    Pawar, Omkar; Patekar, Ashwini; Khan, Ayesha; Kathawate, Laxmi; Haram, Santosh; Markad, Ganesh; Puranik, Vedavati; Salunke-Gawali, Sunita

    2014-02-01

    Derivatives of 2-chloro-3-(n-alkylamino)-1,4-naphthoquinone {n-alkyl: methyl; L-1, ethyl; L-2, propyl; L-3 and butyl; L-4} have been synthesized and characterized by elemental analysis, FT-IR, 1H NMR, UV-visible spectroscopy, LC-MS and single crystal X-ray diffraction studies. Antifungal activity of L-1 to L-4 has been evaluated against Candida tropicalis, Candida albicans and Cladosporium herbarum. The intramolecular hydrogen bonding affects the N-H vibrational frequency in L-2 (3273 cm-1). The single crystal X-ray structure reveal that L-1 and L-3 crystallizes in triclinic P-1, whereas L-2 crystallizes in orthorhombic Pca21 space group. An extensive intra and intermolecular hydrogen bonding interactions were observed in L-1 to L-3 which leads to molecular association. Intramolecular N-H⋯O hydrogen bonding were observed in L-1 to L-3. Moreover π-π stacking interactions were observed between the quinonoid rings of L-1 and L-3, however no such interactions were observed in L-2. An electrochemical study showed molecular association of L-1 to L-4 in DMSO solution. Compounds L-1 to L-4 were found to be potent antifungal agents against all the three strains, especially against C. tropicalis. Amongst these promising antifungal candidates, L-1 showed better activity compared to the clinically administered antifungal drug Amphotericin B and Nitrofurantoin with MIC = 1.25 μg ml-1 and MIC = 0.025 μg ml-1 respectively against C. albicans. Structure and activity relationship (SAR) study suggest a Log P value of ˜2.0 and the cyclic voltammetry studies reveals additional chemical processes for L-1, which exhibits maximum activity against all fungal strains.

  6. Influence of Different Media, Incubation Times, and Temperatures for Determining the MICs of Seven Antifungal Agents against Paracoccidioides brasiliensis by Microdilution

    PubMed Central

    Cruz, R. C.; Werneck, S. M. C.; Oliveira, C. S.; Santos, P. C.; Soares, B. M.; Santos, D. A.

    2013-01-01

    MIC assays with Paracoccidioides brasiliensis, the etiological agent of paracoccidioidomycosis, had been conducted with variable protocols, employing both macrodilution and microdilution tests and including differences in inoculum preparation, media used, incubation periods, and temperatures. Twenty-one clinical and environmental isolates of Paracoccidioides were tested using amphotericin B, itraconazole, ketoconazole, fluconazole, sulfamethoxazole, sulfamethoxazole-trimethoprim, and terbinafine, according to the National Committee for Clinical Laboratory Standards (National Committee for Clinical Laboratory Standards, document M27-A2, 2002), with modifications such as three medium formulations (RPMI 1640 medium, McVeigh and Morton [MVM] medium, and modified Mueller-Hinton [MMH] medium), two incubation temperatures (room temperature [25 to 28°C] and 37°C), and three incubation periods (7, 10, and 15 days). The antifungal activities were also classified as fungicidal or fungistatic. The best results were obtained after 15 days of incubation, which was chosen as the standard incubation time. The MICs for most individual isolates grown for the same length of time at the same temperature varied with the different media used (P < 0.05). Of the isolates, 81% showed transition from the yeast to the mycelial form in RPMI 1640 medium at 37°C, independent of the presence of antifungals. MMH medium appears to be a suitable medium for susceptibility testing of antifungal drugs with P. brasiliensis, except for sulfamethoxazole and the combination of sulfamethoxazole-trimethoprim, for which the MVM medium yielded better results. The incubation temperature influenced the MICs, with, in general, higher MICs at 25°C (mycelial form) than at 37°C (P < 0.05). Based on our results, we tentatively propose a microdilution assay protocol for susceptibility testing of antifungal drugs against Paracoccidioides. PMID:23175254

  7. Azole fungicides - understanding resistance mechanisms in agricultural fungal pathogens.

    PubMed

    Price, Claire L; Parker, Josie E; Warrilow, Andrew G S; Kelly, Diane E; Kelly, Steven L

    2015-08-01

    Plant fungal pathogens can have devastating effects on a wide range of crops, including cereals and fruit (such as wheat and grapes), causing losses in crop yield, which are costly to the agricultural economy and threaten food security. Azole antifungals are the treatment of choice; however, resistance has arisen against these compounds, which could lead to devastating consequences. Therefore, it is important to understand how these fungicides are used and how the resistance arises in order to tackle the problem fully. Here, we give an overview of the problem and discuss the mechanisms that mediate azole resistance in agriculture (point mutations in the CYP51 amino acid sequence, overexpression of the CYP51 enzyme and overexpression of genes encoding efflux pump proteins). © 2015 Society of Chemical Industry.

  8. Evaluating food additives as antifungal agents against Monilinia fructicola in vitro and in hydroxypropyl methylcellulose-lipid composite edible coatings for plums.

    PubMed

    Karaca, Hakan; Pérez-Gago, María B; Taberner, Verònica; Palou, Lluís

    2014-06-02

    Common food preservative agents were evaluated in in vitro tests for their antifungal activity against Monilinia fructicola, the most economically important pathogen causing postharvest disease of stone fruits. Radial mycelial growth was measured in Petri dishes of PDA amended with three different concentrations of the agents (0.01-0.2%, v/v) after 7 days of incubation at 25 °C. Thirteen out of fifteen agents tested completely inhibited the radial growth of the fungus at various concentrations. Among them, ammonium carbonate, ammonium bicarbonate and sodium bicarbonate were the most effective while sodium acetate and sodium formate were the least effective. The effective agents and concentrations were tested as ingredients of hydroxypropyl methylcellulose (HPMC)-lipid edible coatings against brown rot disease on plums previously inoculated with M. fructicola (curative activity). 'Friar' and 'Larry Ann' plums were inoculated with the pathogen, coated with stable edible coatings about 24h later, and incubated at 20 °C and 90% RH. Disease incidence (%) and severity (lesion diameter) were determined after 4, 6, and 8 days of incubation and the 'area under the disease progress stairs' (AUDPS) was calculated. Coatings containing bicarbonates and parabens significantly reduced brown rot incidence in plums, but potassium sorbate, used at 1.0% in the coating formulation, was the most effective agent with a reduction rate of 28.6%. All the tested coatings reduced disease severity to some extent, but coatings containing 0.1% sodium methylparaben or sodium ethylparaben or 0.2% ammonium carbonate or ammonium bicarbonate were superior to the rest, with reduction rates of 45-50%. Overall, the results showed that most of the agents tested in this study had significant antimicrobial activity against M. fructicola and the application of selected antifungal edible coatings is a promising alternative for the control of postharvest brown rot in plums.

  9. Theoretical studies on nitrogen rich energetic azoles.

    PubMed

    Ghule, Vikas Dasharath; Sarangapani, Radhakrishnan; Jadhav, Pandurang M; Tewari, Surya P

    2011-06-01

    Different nitro azole isomers based on five membered heterocyclics were designed and investigated using computational techniques in order to find out the comprehensive relationships between structure and performances of these high nitrogen compounds. Electronic structure of the molecules have been calculated using density functional theory (DFT) and the heat of formation has been calculated using the isodesmic reaction approach at B3LYP/6-31G* level. All designed compounds show high positive heat of formation due to the high nitrogen content and energetic nitro groups. The crystal densities of these energetic azoles have been predicted with different force fields. All the energetic azoles show densities higher than 1.87 g/cm(3). Detonation properties of energetic azoles are evaluated by using Kamlet-Jacobs equation based on the calculated densities and heat of formations. It is found that energetic azoles show detonation velocity about 9.0 km/s, and detonation pressure of 40GPa. Stability of the designed compounds has been predicted by evaluating the bond dissociation energy of the weakest C-NO(2) bond. The aromaticity using nucleus independent chemical shift (NICS) is also explored to predict the stability via delocalization of the π-electrons. Charge on the nitro group is used to assess the impact sensitivity in the present study. Overall, the study implies that all energetic azoles are found to be stable and expected to be the novel candidates of high energy density materials (HEDMs).

  10. Epidemiology of invasive aspergillosis and azole resistance in patients with acute leukaemia: the SEPIA Study.

    PubMed

    Koehler, Philipp; Hamprecht, Axel; Bader, Oliver; Bekeredjian-Ding, Isabelle; Buchheidt, Dieter; Doelken, Gottfried; Elias, Johannes; Haase, Gerhard; Hahn-Ast, Corinna; Karthaus, Meinolf; Kekulé, Alexander; Keller, Peter; Kiehl, Michael; Krause, Stefan W; Krämer, Carolin; Neumann, Silke; Rohde, Holger; La Rosée, Paul; Ruhnke, Markus; Schafhausen, Philippe; Schalk, Enrico; Schulz, Katrin; Schwartz, Stefan; Silling, Gerda; Staib, Peter; Ullmann, Andrew; Vergoulidou, Maria; Weber, Thomas; Cornely, Oliver A; Vehreschild, Maria J G T

    2017-02-01

    Invasive aspergillosis (IA) is a serious hazard to high-risk haematological patients. There are increasing reports of azole-resistant Aspergillus spp. This study assessed the epidemiology of IA and azole-resistant Aspergillus spp. in patients with acute leukaemia in Germany. A prospective multicentre cohort study was performed in German haematology/oncology centres. The incidence of probable and proven aspergillosis according to the revised EORTC/MSG criteria was assessed for all patients with acute leukaemia [acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL)]. Cases were documented into a web-based case report form, and centres provided data on standards regarding prophylactic and diagnostic measures. Clinical isolates were screened centrally for azole resistance and, if applicable, underlying resistance mechanisms were analysed. Between September 2011 and December 2013, 179 cases of IA [6 proven (3.4%) and 173 probable (96.6%)] were diagnosed in 3067 patients with acute leukaemia. The incidence of IA was 6.4% among 2440 AML patients and 3.8% among 627 ALL patients. Mortality at Day 84 was 33.8% (49/145) and attributable mortality was 26.9% (39/145). At Day 84, 53 patients (29.6%) showed a complete response, 25 (14.0%) a partial response and 17 (9.5%) a deterioration or failure. A total of 77 clinical Aspergillus fumigatus isolates were collected during the study period. Two episodes of azole-resistant IA (1.1%) were caused by a TR/L98H mutation in the cyp51A gene. With only two cases of IA due to azole-resistant A. fumigatus, a change of antifungal treatment practices in Germany does not appear warranted currently.

  11. Cryptic Species and Azole Resistance in the Aspergillus niger Complex▿†

    PubMed Central

    Howard, Susan J.; Harrison, Elizabeth; Bowyer, Paul; Varga, Janos; Denning, David W.

    2011-01-01

    Aspergillus niger is a common clinical isolate. Multiple species comprise the Aspergillus section Nigri and are separable using sequence data. The antifungal susceptibility of these cryptic species is not known. We determined the azole MICs of 50 black aspergilli, 45 from clinical specimens, using modified EUCAST (mEUCAST) and Etest methods. Phylogenetic trees were prepared using the internal transcribed spacer, beta-tubulin, and calmodulin sequences to identify strains to species level and the results were compared with those obtained with cyp51A sequences. We attempted to correlate cyp51A mutations with azole resistance. Etest MICs were significantly different from mEUCAST MICs (P < 0.001), with geometric means of 0.77 and 2.79 mg/liter, respectively. Twenty-six of 50 (52%) isolates were itraconazole resistant by mEUCAST (MICs > 8 mg/liter), with limited cross-resistance to other azoles. Using combined beta-tubulin/calmodulin sequences, the 45 clinical isolates grouped into 5 clades, A. awamori (55.6%), A. tubingensis (17.8%), A. niger (13.3%), A. acidus (6.7%), and an unknown group (6.7%), none of which were morphologically distinguishable. Itraconazole resistance was found in 36% of the isolates in the A. awamori group, 90% of the A. tubingensis group, 33% of the A. niger group, 100% of the A. acidus group, and 67% of the unknown group. These data suggest that cyp51A mutations in section Nigri may not play as important a role in azole resistance as in A. fumigatus, although some mutations (G427S, K97T) warrant further study. Numerous cryptic species are found in clinical isolates of the Aspergillus section Nigri and are best reported as “A. niger complex” by clinical laboratories. Itraconazole resistance was common in this data set, but azole cross-resistance was unusual. The mechanism of resistance remains obscure. PMID:21768508

  12. Asexual sporulation facilitates adaptation: The emergence of azole resistance in Aspergillus fumigatus.

    PubMed

    Zhang, Jianhua; Debets, Alfons J M; Verweij, Paul E; Melchers, Willem J G; Zwaan, Bas J; Schoustra, Sijmen E

    2015-10-01

    Understanding the occurrence and spread of azole resistance in Aspergillus fumigatus is crucial for public health. It has been hypothesized that asexual sporulation, which is abundant in nature, is essential for phenotypic expression of azole resistance mutations in A. fumigatus facilitating subsequent spread through natural selection. Furthermore, the disease aspergilloma is associated with asexual sporulation within the lungs of patients and the emergence of azole resistance. This study assessed the evolutionary advantage of asexual sporulation by growing the fungus under pressure of one of five different azole fungicides over seven weeks and by comparing the rate of adaptation between scenarios of culturing with and without asexual sporulation. Results unequivocally show that asexual sporulation facilitates adaptation. This can be explained by the combination of more effective selection because of the transition from a multicellular to a unicellular stage, and by increased mutation supply due to the production of spores, which involves numerous mitotic divisions. Insights from this study are essential to unravel the resistance mechanisms of sporulating pathogens to chemical compounds and disease agents in general, and for designing strategies that prevent or overcome the emerging threat of azole resistance in particular.

  13. Antifungal Susceptibility Analysis of Clinical Isolates of Candida parapsilosis in Iran

    PubMed Central

    LOTFALI, Ensieh; KORDBACHEH, Parivash; MIRHENDI, Hossein; ZAINI, Farideh; GHAJARI, Ali; MOHAMMADI, Rasoul; NOORBAKHSH, Fatemeh; MOAZENI, Maryam; FALLAHI, Aliakbar; REZAIE, Sassan

    2016-01-01

    Background: Candida parapsilosis is an emergent agent of invasive fungal infections. This yeast is one of the five most widespread yeasts concerned in invasive candidiasis. C. parapsilosis stands out as the second most common yeast species isolated from patients with bloodstream infections especially in neonates with catheter. Recently several reports suggested that its reduced susceptibility to azoles and polyene might become a cause for clinical concern, although C. parapsilosis is not believed to be intensely prone to the development of antifungal resistance. Methods: In the present report, One hundred and twenty clinical isolates of C. parapsilosis complex were identified and differentiated by using PCR-RFLP analysis. The isolates were then analyzed to determine their susceptibility profile to fluconazole (FLU), itraconazole (ITC) and amphotericin B. The minimum inhibitory concentration (MIC) results were analyzed according to the standard CLSI guide. Results: All of isolates were identified as C. parapsilosis. No C. metapsilosis and C. orthopsilosis strains were found. Evaluation of the antifungal susceptibility profile showed that only three (2.5%) C. parapsilosis were resistant to fluconazole, three (2.5%) C. parapsilosis were resistant to itraconazole and two (1.7%) C. parapsilosis were amphotericin B resistant. Conclusion: Profiles in clinical isolates of C. parapsilosis can provide important information for the control of antifungal resistance as well as distribution and susceptibility profiles in populations. PMID:27141494

  14. High-performance liquid chromatographic assay for the determination of novel triazole antifungal agents in tissue. Application to tissue distribution studies.

    PubMed

    Khan, J K; Montaseri, H; Poglod, M; Bu, H Z; Daneshtalab, M; Micetich, R G

    2000-08-01

    A simple and rugged reversed-phase high-performance liquid chromatographic method with ultraviolet absorbance detection at 263 nm was developed and validated for the analysis of novel triazole antifungal agents SYN-2869 and its derivatives in tissues. The method involved homogenization with 0.01 M phosphate buffer (pH 7.8) for lung, brain and spleen tissues. The liver and kidneys were homogenized with acetonitrile:acetone (1:1). The plasma proteins were precipitated with ice-cold acetonitrile and supernatent was evaporated to dryness. The reconstituted samples were injected onto an HPLC system. SYN-2869 was separated from the matrix components on a symmetry C(18) column using a aqueous mobile phase of acetonitrile and water with a flow rate of 1 mL/min. A step gradient of 40-80% acetonitrile eluted SYN-2869 and the internal standard (SYN-2506). The linear range was 0.5-10 microgram/g (r(2) > 0.99). The limit of quantitation was 0.5 microgram/g. The inter-day precision and accuracy for SYN 2869 standard concentration were from 2.6 to 7.4% and from -1.56 to +3.29%, respectively. The method was applied to tissue samples collected from single intravenous administration to mice to evaluate the distribution of these novel antifungal agents to different tissues.

  15. Lipopeptides, a novel protein, and volatile compounds contribute to the antifungal activity of the biocontrol agent Bacillus atrophaeus CAB-1.

    PubMed

    Zhang, Xiaoyun; Li, Baoqing; Wang, Ye; Guo, Qinggang; Lu, Xiuyun; Li, Shezeng; Ma, Ping

    2013-11-01

    Bacillus atrophaeus CAB-1 displays a high inhibitory activity against various fungal pathogens and suppresses cucumber powdery mildew and tomato gray mold. We extracted and identified lipopeptides and secreted proteins and volatile compounds produced by strain CAB-1 to investigate the mechanisms involved in its biocontrol performance. In vitro assays indicated all three types of products contributed to the antagonistic activity against the fungal pathogen Botrytis cinerea. Each of these components also effectively prevented the occurrence of the cucumber powdery mildew caused by Sphaerotheca fuliginea under greenhouse conditions. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry revealed that the major bioactive lipopeptide was fengycin A (C15-C17). We isolated the crude-secreted proteins of CAB-1 and purified a fraction with antifungal activity. This protein sequence shared a high identity with a putative phage-related pre-neck appendage protein, which has not been reported as an antifungal factor. The volatile compounds produced by CAB-1 were complex, including a range of alcohols, phenols, amines, and alkane amides. O-anisaldehyde represented one of the most abundant volatiles with the highest inhibition on the mycelial growth of B. cinerea. To our knowledge, this is the first report on profiling three types of antifungal substances in Bacilli and demonstrating their contributions to plant disease control.

  16. Azole resistance in Candida spp. isolated from Catú Lake, Ceará, Brazil: an efflux-pump-mediated mechanism

    PubMed Central

    Brilhante, Raimunda S.N.; Paiva, Manoel A.N.; Sampaio, Célia M.S.; Castelo-Branco, Débora S.C.M.; Teixeira, Carlos E.C.; de Alencar, Lucas P.; Bandeira, Tereza J.P.G.; Monteiro, André J.; Cordeiro, Rossana A.; Pereira-Neto, Waldemiro A.; Sidrim, José J.C.; Moreira, José L.B.; Rocha, Marcos F.G.

    2016-01-01

    Since, there is no study reporting the mechanism of azole resistance among yeasts isolated from aquatic environments; the present study aims to investigate the occurrence of antifungal resistance among yeasts isolated from an aquatic environment, and assess the efflux-pump activity of the azole-resistant strains to better understand the mechanism of resistance for this group of drugs. For this purpose, monthly water and sediment samples were collected from Catú Lake, Ceará, Brazil, from March 2011 to February 2012. The obtained yeasts were identified based on morphological and biochemical characteristics. Of the 46 isolates, 37 were Candida spp., 4 were Trichosporon asahii, 3 were Cryptococcus laurentii, 1 Rhodotorula mucilaginosa, and 1 was Kodamaea ohmeri. These isolates were subjected to broth microdilution assay with amphotericin B, itraconazole, and fluconazole, according to the methodology standardized by the Clinical and Laboratory Standards Institute (CLSI). The minimum inhibitory concentrations (MICs) of amphotericin B, itraconazole, and fluconazole were 0.03125–2 μg/mL, 0.0625 to ≥16 μg/mL, and 0.5 to ≥64 μg/mL, respectively, and 13 resistant azole-resistant Candida isolates were detected. A reduction in the azole MICs leading to the phenotypical reversal of the azole resistance was observed upon addition of efflux-pump inhibitors. These findings suggest that the azole resistance among environmental Candida spp. is most likely associated with the overexpression of efflux-pumps. PMID:26887224

  17. Activity of a Long-Acting Echinocandin (CD101) and Seven Comparator Antifungal Agents Tested against a Global Collection of Contemporary Invasive Fungal Isolates in the SENTRY 2014 Antifungal Surveillance Program

    PubMed Central

    Pfaller, Michael A.; Messer, Shawn A.; Rhomberg, Paul R.

    2017-01-01

    ABSTRACT The activity of CD101 and comparator antifungal agents against 606 invasive fungal isolates collected worldwide during 2014 was evaluated using the Clinical and Laboratory Standards Institute (CLSI) method. All Candida albicans (n = 251), Candida tropicalis (n = 51), Candida krusei (n = 16), and Candida dubliniensis (n = 11) isolates were inhibited by ≤0.12 μg/ml of CD101 and were susceptible or showed wild-type susceptibility to the other echinocandins tested. Five C. glabrata isolates (n = 100) displayed CD101 MIC values of 1 to 4 μg/ml, had elevated MICs of caspofungin (2 to >8 μg/ml), anidulafungin (2 to 4 μg/ml), and micafungin (2 to 4 μg/ml), and carried mutations on fks1 and fks2. Candida parapsilosis (n = 92) and Candida orthopsilosis (n = 10) displayed higher CD101 MIC values (ranges, 0.5 to 4 μg/ml and 0.12 to 2 μg/ml, respectively), and similar results were observed for the other echinocandins tested. Fluconazole resistance was noted among 11.0% of Candida glabrata isolates, 4.3% of C. parapsilosis isolates, and 2.0% of C. albicans and C. tropicalis isolates. The activity of CD101 against Aspergillus fumigatus (n = 56) was similar to that of micafungin and 2-fold greater than that of caspofungin but less than that of anidulafungin. These isolates had wild-type susceptibility to itraconazole, voriconazole, and posaconazole. The echinocandins had limited activity against Cryptococcus neoformans (n = 19). CD101 was as active as the other echinocandins against common fungal organisms recovered from patients with invasive fungal infections. The long half-life profile is very desirable for the prevention and treatment of serious fungal infections, especially in patients who can then be discharged from the hospital to complete antifungal therapy on an outpatient basis. PMID:28052853

  18. Clotrimazole as a Potent Agent for Treating the Oomycete Fish Pathogen Saprolegnia parasitica through Inhibition of Sterol 14α-Demethylase (CYP51)

    PubMed Central

    Warrilow, Andrew G. S.; Hull, Claire M.; Rolley, Nicola J.; Parker, Josie E.; Nes, W. David; Smith, Stephen N.

    2014-01-01

    A candidate CYP51 gene encoding sterol 14α-demethylase from the fish oomycete pathogen Saprolegnia parasitica (SpCYP51) was identified based on conserved CYP51 residues among CYPs in the genome. It was heterologously expressed in Escherichia coli, purified, and characterized. Lanosterol, eburicol, and obtusifoliol bound to purified SpCYP51 with similar binding affinities (Ks, 3 to 5 μM). Eight pharmaceutical and six agricultural azole antifungal agents bound tightly to SpCYP51, with posaconazole displaying the highest apparent affinity (Kd, ≤3 nM) and prothioconazole-desthio the lowest (Kd, ∼51 nM). The efficaciousness of azole antifungals as SpCYP51 inhibitors was confirmed by 50% inhibitory concentrations (IC50s) of 0.17 to 2.27 μM using CYP51 reconstitution assays. However, most azole antifungal agents were less effective at inhibiting S. parasitica, Saprolegnia diclina, and Saprolegnia ferax growth. Epoxiconazole, fluconazole, itraconazole, and posaconazole failed to inhibit Saprolegnia growth (MIC100, >256 μg ml−1). The remaining azoles inhibited Saprolegnia growth only at elevated concentrations (MIC100 [the lowest antifungal concentration at which growth remained completely inhibited after 72 h at 20°C], 16 to 64 μg ml−1) with the exception of clotrimazole, which was as potent as malachite green (MIC100, ∼1 μg ml−1). Sterol profiles of azole-treated Saprolegnia species confirmed that endogenous CYP51 enzymes were being inhibited with the accumulation of lanosterol in the sterol fraction. The effectiveness of clotrimazole against SpCYP51 activity (IC50, ∼1 μM) and the concentration inhibiting the growth of Saprolegnia species in vitro (MIC100, ∼1 to 2 μg ml−1) suggest that clotrimazole could be used against Saprolegnia infections, including as a preventative measure by pretreatment of fish eggs, and for freshwater-farmed fish as well as in leisure activities. PMID:25085484

  19. Direct, Regioselective N-Alkylation of 1,3-Azoles.

    PubMed

    Chen, Shuai; Graceffa, Russell F; Boezio, Alessandro A

    2016-01-04

    Regioselective N-alkylation of 1,3-azoles is a valuable transformation. Organomagnesium reagents were discovered to be competent bases to affect regioselective alkylation of various 1,3-azoles. Counterintuitively, substitution selectively occurred at the more sterically hindered nitrogen atom. Numerous examples are provided, on varying 1,3-azole scaffolds, with yields ranging from 25 to 95%.

  20. Prospective Multicenter International Surveillance of Azole Resistance in Aspergillus fumigatus

    PubMed Central

    Arendrup, M.C.; Warris, A.; Lagrou, K.; Pelloux, H.; Hauser, P.M.; Chryssanthou, E.; Mellado, E.; Kidd, S.E.; Tortorano, A.M.; Dannaoui, E.; Gaustad, P.; Baddley, J.W.; Uekötter, A.; Lass-Flörl, C.; Klimko, N.; Moore, C.B.; Denning, D.W.; Pasqualotto, A.C.; Kibbler, C.; Arikan-Akdagli, S.; Andes, D.; Meletiadis, J.; Naumiuk, L.; Nucci, M.; Melchers, W.J.G.; Verweij, P.E.

    2015-01-01

    To investigate azole resistance in clinical Aspergillus isolates, we conducted prospective multicenter international surveillance. A total of 3,788 Aspergillus isolates were screened in 22 centers from 19 countries. Azole-resistant A. fumigatus was more frequently found (3.2% prevalence) than previously acknowledged, causing resistant invasive and noninvasive aspergillosis and severely compromising clinical use of azoles. PMID:25988348

  1. New facets of antifungal therapy.

    PubMed

    Chang, Ya-Lin; Yu, Shang-Jie; Heitman, Joseph; Wellington, Melanie; Chen, Ying-Lien

    2017-02-17

    Invasive fungal infections remain a major cause of morbidity and mortality in immunocompromised patients, and such infections are a substantial burden to healthcare systems around the world. However, the clinically available armamentarium for invasive fungal diseases is limited to 3 main classes (i.e., polyenes, triazoles, and echinocandins), and each has defined limitations related to spectrum of activity, development of resistance, and toxicity. Further, current antifungal therapies are hampered by limited clinical efficacy, high rates of toxicity, and significant variability in pharmacokinetic properties. New antifungal agents, new formulations, and novel combination regimens may improve the care of patients in the future by providing improved strategies to combat challenges associated with currently available antifungal agents. Likewise, therapeutic drug monitoring may be helpful, but its present use remains controversial due to the lack of available data. This article discusses new facets of antifungal therapy with a focus on new antifungal formulations and the synergistic effects between drugs used in combination therapy.

  2. In Vitro Interactions between Non-Steroidal Anti-Inflammatory Drugs and Antifungal Agents against Planktonic and Biofilm Forms of Trichosporon asahii

    PubMed Central

    Cong, Lin; Lu, Xuelian

    2016-01-01

    Increasing drug resistance has brought enormous challenges to the management of Trichosporon spp. infections. The in vitro antifungal activities of non-steroidal anti-inflammatory drugs (NSAIDs) against Candida spp. and Cryptococcus spp. were recently discovered. In the present study, the in vitro interactions between three NSAIDs (aspirin, ibuprofen and diclofenac sodium) and commonly used antifungal agents (fluconazole, itraconazole, voriconazole, caspofungin and amphotericin B) against planktonic and biofilm cells of T. asahii were evaluated using the checkerboard microdilution method. The spectrophotometric method and the XTT reduction assay were used to generate data on biofilm cells. The fractional inhibitory concentration index (FICI) and the ΔE model were compared to interpret drug interactions. Using the FICI, the highest percentages of synergistic effects against planktonic cells (86.67%) and biofilm cells (73.33%) were found for amphotericin B/ibuprofen, and caspofungin/ibuprofen showed appreciable percentages (73.33% for planktonic form and 60.00% for biofilm) as well. We did not observe antagonism. The ΔE model gave consistent results with FICI (86.67%). Our findings suggest that amphotericin B/ibuprofen and caspofungin/ibuprofen combinations have potential effects against T. asahii. Further in vivo and animal studies to investigate associated mechanisms need to be conducted. PMID:27275608

  3. Terbinafine in combination with other antifungal agents for treatment of resistant or refractory mycoses: investigating optimal dosing regimens using a physiologically based pharmacokinetic model.

    PubMed

    Dolton, Michael J; Perera, Vidya; Pont, Lisa G; McLachlan, Andrew J

    2014-01-01

    Terbinafine is increasingly used in combination with other antifungal agents to treat resistant or refractory mycoses due to synergistic in vitro antifungal activity; high doses are commonly used, but limited data are available on systemic exposure, and no assessment of pharmacodynamic target attainment has been made. Using a physiologically based pharmacokinetic (PBPK) model for terbinafine, this study aimed to predict total and unbound terbinafine concentrations in plasma with a range of high-dose regimens and also calculate predicted pharmacodynamic parameters for terbinafine. Predicted terbinafine concentrations accumulated significantly during the first 28 days of treatment; the area under the concentration-time curve (AUC)/MIC ratios and AUC for the free, unbound fraction (fAUC)/MIC ratios increased by 54 to 62% on day 7 of treatment and by 80 to 92% on day 28 compared to day 1, depending on the dose regimen. Of the high-dose regimens investigated, 500 mg of terbinafine taken every 12 h provided the highest systemic exposure; on day 7 of treatment, the predicted AUC, maximum concentration (Cmax), and minimum concentration (Cmin) were approximately 4-fold, 1.9-fold, and 4.4-fold higher than with a standard-dose regimen of 250 mg once daily. Close agreement was seen between the concentrations predicted by the PBPK model and the observed concentrations, indicating good predictive performance. This study provides the first report of predicted terbinafine exposure in plasma with a range of high-dose regimens.

  4. Synthesis and biological evaluation of a new series of N-acyldiamines as potential antibacterial and antifungal agents.

    PubMed

    Ferreira, Bianca da S; de Almeida, Angelina M; Nascimento, Thiago C; de Castro, Pedro P; Silva, Vania L; Diniz, Claúdio G; Le Hyaric, Mireille

    2014-10-01

    In continuation of our efforts to find new antimicrobial compounds, series of fatty N-acyldiamines were prepared from fatty methyl esters and 1,2-ethylenediamine, 1,3-propanediamine or 1,4-butanediamine. The synthesized compounds were screened for their antibacterial activity against Gram-positive bacteria (Staphylococcus aureus, Staphylococcus epidermidis), Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and for their antifungal activity against four species of Candida (C. albicans, C. tropicalis, C. glabrata and C. parapsilosis). Compounds 5a (N-(2-aminoethyl)dodecanamide), 5b (N-(2-aminoethyl)tetracanamide) and 6d (N-(3-aminopropyl)oleamide) were the most active against Gram-positive bacteria, with MIC values ranging from 1 to 16μg/mL and were evaluated for their activity against 21 clinical isolates of methicillin-resistant S. aureus. All the compounds exhibited good to moderate antifungal activity. Compared to chloramphenicol, compound 6b displayed a similar activity (MIC50=16μg/mL). A positive correlation could be established between lipophilicity and biological activity.

  5. Structure of a secreted aspartic protease from C. albicans complexed with a potent inhibitor: implications for the design of antifungal agents.

    PubMed Central

    Abad-Zapatero, C.; Goldman, R.; Muchmore, S. W.; Hutchins, C.; Stewart, K.; Navaza, J.; Payne, C. D.; Ray, T. L.

    1996-01-01

    The three-dimensional structure of a secreted aspartic protease from Candida albicans complexed with a potent inhibitor reveals variations on the classical aspartic protease theme that dramatically alter the specificity of this class of enzymes. The structure presents: (1) an 8-residue insertion near the first disulfide (Cys 45-Cys 50, pepsin numbering) that results in a broad flap extending toward the active site; (2) a 7-residue deletion replacing helix hN2 (Ser 110-Tyr 114), which enlarges the S3 pocket; (3) a short polar connection between the two rigid body domains that alters their relative orientation and provides certain specificity; and (4) an ordered 11-residue addition at the carboxy terminus. The inhibitor binds in an extended conformation and presents a branched structure at the P3 position. The implications of these findings for the design of potent antifungal agents are discussed. PMID:8845753

  6. In vitro and in vivo antifungal activities of the essential oils of various plants against tomato grey mould disease agent Botrytis cinerea.

    PubMed

    Soylu, Emine Mine; Kurt, Sener; Soylu, Soner

    2010-10-15

    The aim of this study was to find an alternative to synthetic fungicides currently used in the control of devastating fungal pathogen Botrytis cinerea, the causal agent of grey mould disease of tomato. Antifungal activities of essential oils obtained from aerial parts of aromatic plants, which belong to the Lamiacea family such as origanum (Origanum syriacum L. var. bevanii), lavender (Lavandula stoechas L. var. stoechas) and rosemary (Rosmarinus officinalis L.), were investigated against B. cinerea. Contact and volatile phase effects of different concentrations of the essential oils were found to inhibit the growth of B. cinerea in a dose-dependent manner. Volatile phase effects of essential oils were consistently found to be more effective on fungal growth than contact phase effect. A volatile vapour of origanum oil at 0.2 μg/ml air was found to completely inhibit the growth of B. cinerea. Complete growth inhibition of pathogen by essential oil of lavender and rosemary was, however, observed at 1.6 μg/ml air concentrations. For the determination of the contact phase effects of the tested essential oils, origanum oil at 12.8 μg/ml was found to inhibit the growth of B. cinerea completely. Essential oils of rosemary and lavender were inhibitory at relatively higher concentrations (25.6 μg/ml). Spore germination and germ tube elongation were also inhibited by the essential oils tested. Light and scanning electron microscopic (SEM) observations revealed that the essential oils cause considerable morphological degenerations of the fungal hyphae such as cytoplasmic coagulation, vacuolations, hyphal shrivelling and protoplast leakage and loss of conidiation. In vivo assays with the origanum essential oil, being the most efficient essential oil, under greenhouse conditions using susceptible tomato plants resulted in good protection against grey mould severity especially as a curative treatment. This study has demonstrated that the essential oils are potential and

  7. In vitro susceptibility of e.faecalis and c.albicans isolates from apical periodontitis to common antimicrobial agents, antibiotics and antifungal medicaments

    PubMed Central

    Yoldas, Oguz; Yilmaz, Sehnaz; Akcimen, Beril; Seydaoglu, Gulsah; Kipalev, Arzu; Koksal, Fatih

    2012-01-01

    The aim of this study was to evaluate in vitro antimicrobial activity of 4 antibiotic agents (for E.faecalis) and 4 antifungal agents (for C.albicans) by agar dilution method. Additionally, modified strip diffusion method was used for detection of in vitro antimicrobial activities of 5% NaOCl, 2.5% NaOCl, 17% EDTA and 2% CHX and agar diffusion method for detection of in vitro susceptibilities of three intracanal medicaments for 18 E.faecalis and 18 C.albicans isolates from primary and secondary root canal infection. Isolates were recovered from 231 endodontic samples of patients, with the need of root canal treatment and retreatment. All tested E.faecalis isolates showed resistance to antibiotics. For irrigation solutions, 2% CHX was more effective in eliminating E.faecalis but 5% NaOCl showed larger inhibition zone than 2.5% NaOCl, 17% EDTA and 2% CHX. For intracanal medication, Ca(OH)2-CHX worked efficiently in killing E.faecalis isolates compared to Ca(OH)2-Steril saline solution, Ca(OH)2-Glycerin. For C.albicans, 18 isolates were susceptible to amphotericin B, nistatin, fluconazole but showed resistance to ketoconazole. 5% NaOCl was more effective in eliminating and produced larger inhibition zone compared to 2.5% NaOCl, 17% EDTA and 2% CHX. Ca(OH)2-Glycerin intracanal medication was better in eliminating C.albicans isolates and produced larger inhibition zone compared to other Ca(OH)2 medicaments. Key words:E.faecalis, C.albicans, antimicrobial, antibiotic, antifungal. PMID:24558517

  8. Antifungal Amphiphilic Aminoglycosides

    PubMed Central

    Chang, C.-W. T.; Takemoto, J.Y.

    2014-01-01

    The attachment of alkyl and other hydrophobic groups to traditional antibacterial kanamycins and neomycins creates amphiphilic aminoglycosides with altered antimicrobial properties. In this review, we summarize the discovery of amphiphilic kanamycins that are antifungal, but not antibacterial, and that inhibit the growth of fungi by perturbation of plasma membrane functions. With low toxicities against plant and mammalian cells, they appear to specifically target the fungal plasma membrane. These new antifungal agents offer new options for fighting fungal pathogens and are examples of reviving old drugs to confront new therapeutic challenges. PMID:25110571

  9. Novel triazole antifungal drugs: focus on isavuconazole, ravuconazole and albaconazole.

    PubMed

    Pasqualotto, Alessandro C; Thiele, Karoline O; Goldani, Luciano Z

    2010-02-01

    Azoles are important compounds for the treatment of fungal infections. This review focuses on three azoles: isavuconazole, ravuconazole and albaconazole (Stiefel). These drugs exhibit a broad spectrum of activity in vitro, including activity against several fungal isolates that are resistant to other azoles. However, poor or limited activity of these compounds has been demonstrated against species of Fusarium and Scedosporium, as well as against Zygomycetes. As isavuconazole and ravuconazole have been developed both as intravenous and oral formulations, these compounds are suitable candidates for the treatment of various invasive fungal diseases. Most clinical trials with albaconazole have targeted mucocutaneous fungal infections. Although all of these agents appear to be well tolerated, cross-resistance is a concern in the azole family of compounds.

  10. Novel point mutations in the ERG11 gene in clinical isolates of azole resistant Candida species.

    PubMed

    Silva, Danielly Beraldo dos Santos; Rodrigues, Luana Mireli Carbonera; Almeida, Adriana Araújo de; Oliveira, Kelly Mari Pires de; Grisolia, Alexéia Barufatti

    2016-03-01

    The azoles are the class of medications most commonly used to fight infections caused by Candida sp. Typically, resistance can be attributed to mutations in ERG11 gene (CYP51) which encodes the cytochrome P450 14α-demethylase, the primary target for the activity of azoles. The objective of this study was to identify mutations in the coding region of theERG11 gene in clinical isolates of Candida species known to be resistant to azoles. We identified three new synonymous mutations in the ERG11 gene in the isolates of Candida glabrata (C108G, C423T and A1581G) and two new nonsynonymous mutations in the isolates of Candida krusei--A497C (Y166S) and G1570A (G524R). The functional consequence of these nonsynonymous mutations was predicted using evolutionary conservation scores. The G524R mutation did not have effect on 14α-demethylase functionality, while the Y166S mutation was found to affect the enzyme. This observation suggests a possible link between the mutation and dose-dependent sensitivity to voriconazole in the clinical isolate of C. krusei. Although the presence of the Y166S in phenotype of reduced azole sensitivity observed in isolate C. krusei demands investigation, it might contribute to the search of new therapeutic agents against resistant Candida isolates.

  11. Intermolecular interaction of voriconazole analogues with model membrane by DSC and NMR, and their antifungal activity using NMR based metabolic profiling.

    PubMed

    Kalamkar, Vaibhav; Joshi, Mamata; Borkar, Varsha; Srivastava, Sudha; Kanyalkar, Meena

    2013-11-01

    The development of novel antifungal agents with high susceptibility and increased potency can be achieved by increasing their overall lipophilicity. To enhance the lipophilicity of voriconazole, a second generation azole antifungal agent, we have synthesized its carboxylic acid ester analogues, namely p-methoxybenzoate (Vpmb), toluate (Vtol), benzoate (Vbz) and p-nitrobenzoate (Vpnb). The intermolecular interactions of these analogues with model membrane have been investigated using nuclear magnetic resonance (NMR) and differential scanning calorimetric (DSC) techniques. The results indicate varying degree of changes in the membrane bilayer's structural architecture and physico-chemical characteristics which possibly can be correlated with the antifungal effects via fungal membrane. Rapid metabolite profiling of chemical entities using cell preparations is one of the most important steps in drug discovery. We have evaluated the effect of synthesized analogues on Candida albicans. The method involves real time (1)H NMR measurement of intact cells monitoring NMR signals from fungal metabolites which gives Metabolic End Point (MEP). This is then compared with Minimum Inhibitory Concentration (MIC) determined using conventional methods. Results indicate that one of the synthesized analogues, Vpmb shows reasonably good activity.

  12. cis-Acting Elements within the Candida albicans ERG11 Promoter Mediate the Azole Response through Transcription Factor Upc2p▿

    PubMed Central

    Oliver, Brian G.; Song, Jia L.; Choiniere, Jake H.; White, Theodore C.

    2007-01-01

    The azole antifungal drugs are used to treat infections caused by Candida albicans and other fungi. These drugs interfere with the biosynthesis of ergosterol, the major sterol in fungal cells, by inhibiting an ergosterol biosynthetic enzyme, lanosterol 14 α-demethylase, encoded by the ERG11 gene. In vitro, these drugs as well as other ergosterol biosynthesis inhibitors increase ERG11 mRNA expression by activation of the ERG11 promoter. The signal for this activation most likely is the depletion of ergosterol, the end product of the pathway. To identify cis-acting regulatory elements that mediate this activation, ERG11 promoter fragments have been fused to the luciferase reporter gene from Renilla reniformis. Promoter deletions and linker scan mutations localized the region important for azole induction to a segment from bp −224 to −251 upstream of the start codon, specifically two 7-bp sequences separated by 13 bp. These sequences form an imperfect inverted repeat. The region is recognized by the transcription factor Upc2p and functions as an enhancer of transcription, as it can be placed upstream of a heterologous promoter in either direction, resulting in the azole induction of that promoter. The promoter constructs are not azole inducible in the upc2/upc2 homozygous deletion, demonstrating that Upc2p controls the azole induction of ERG11. These results identify an azole-responsive enhancer element (ARE) in the ERG11 promoter that is controlled by the Upc2p transcription factor. No other ARE is present in the promoter. Thus, this ARE and Upc2p are necessary and sufficient for azole induction of ERG11. PMID:17951521

  13. A substituted sulfonamide and its Co (II), Cu (II), and Zn (II) complexes as potential antifungal agents.

    PubMed

    Diaz, Jorge R A; Fernández Baldo, Martín; Echeverría, Gustavo; Baldoni, Héctor; Vullo, Daniela; Soria, Delia B; Supuran, Claudiu T; Camí, Gerardo E

    2016-01-01

    A sulfonamide 1-tosyl-1-H-benzo(d)imidazol-2-amine (TBZA) and three new complexes of Co(II), Cu(II), and Zn(II) have been synthesized. The compounds have been characterized by elemental analyses, FTIR, (1)H, and (13)C-NMR spectroscopy. The structure of the TBZA, and its Co(II) and Cu(II) complexes, was determined by X-ray diffraction methods. TBZA and its Co(II) complex crystallize in the triclinic P-1 space group, while the Cu(II) complex crystallizes in the monoclinic P21/c space group. Antifungal activity was screened against eight pathogenic yeasts: Candida albicans (DMic 972576), Candida krusei (DMic 951705), Candida glabrata (DMic 982882), Candida tropicalis (DMic 982884), Candida dubliniensis (DMic 93695), Candida guilliermondii (DMic 021150), Cryptococcus neoformans (ATCC 24067), and Cryptococcus gattii (ATCC MYA-4561). Results on the inhibition of various human (h) CAs, hCA I, II, IV, VII, IX, and XII, and pathogenic beta and gamma CAs are also reported.

  14. Frequency of clinically isolated strains of oral Candida species at Kagoshima University Hospital, Japan, and their susceptibility to antifungal drugs in 2006–2007 and 2012–2013

    PubMed Central

    2014-01-01

    Background The isolation frequency and susceptibility to antifungal agents of oral Candida isolates from patients with oral candidiasis (OC) were compared between studies conducted in 2006–2007 and 2012–2013. Methods A total158 strains was isolated from 112 patients who visited Kagoshima University Hospital for the treatment of OC during the 14-month period from February 2012 and March 2013, and evaluated on the isolation frequency of each Candida strain and the susceptibility against antifungal drugs as compared to those evaluated in 2006–2007. Results There was a higher frequency of xerostomia as a chief complaint and of autoimmune disease in the 2012–2013 study than in the 2006–2007 study. More than 95% of Candida isolates were C. albicans and C. glabrata. In addition, the proportion of the latter increased from 12.3% in the 2006–2007 study to 23.4% in the 2012–2013 study, while the proportion of the former decreased from 86.2% to 72.8%, respectively. C. albicans was isolated in almost all patients, while C. glabrata was only isolated concomitantly with C. albicans. Minimal inhibitory concentrations (MICs) were not significantly different between groups with a few exceptions. Candida isolates, of which MICs surpassed break points, apparently increased for miconazole and itraconazole against C. glabrata in the 2012–2013 study, but this was not statistically significant. As a result, more cases of autoimmune disease, a greater number of C. glabrata isolates, and higher resistance to azoles were seen in the 2012–2013 study than in the 2006–2007 study. Conclusion These data indicate that with recent increases in C. glabrata infection, a causative fungus of OC, and in C. glabrata resistance to azoles, caution is needed in the selection of antifungal drugs for the treatment of OC. PMID:24552136

  15. [Species distribution and antifungal susceptibility of Candida spp. causing superficial mycosis. Coro, Falcon state, Venezuela].

    PubMed

    Saúl-García, Yotsabeth; Humbría-García, Leyla; Hernández-Valles, Rosaura

    2015-09-01

    Candida species other than C. albicans are often described as causative agents of superficial mycosis and are more resistant to treatment with azoles. In order to determine the distribution of species and in vitro antifungal susceptibility of Candida spp., one ambispective study, which analyzed 18 yeast isolates obtained from samples from patients diagnosed with superficial mycosis, was performed. Taxonomic identification was performed by macroscopic visualization of the growth characteristics in chromogenic agar and by conventional methods. The susceptibility to fluconazole and voriconazole was evaluated by the disc diffusion method. Most of the isolates (88.8%), came from nail samples. C. parapsilosis was the most common species, followed by C. tropicalis, C. albicans and C. krusei, which confirmed the prevalence of non-albicans species as a cause of superficial mycoses. The pattern of susceptibility to fluconazole and voriconazole was similar: all isolates of C. parapsilosis and C. albicans were susceptible, while 83.3% of C. tropicalis showed sensitivity to both antifungals. C. krusei, fluconazole-resistant species showed intermediate susceptibility io voriconazole. The use of chromogenic agar allowed to detect mixed infections in nail samples, involving Candida spp. and C. tropicalis in one case, the latter with resistance to both fluconazole and voriconazole. The results demonstrate the importance of species identification and susceptibility testing to avoid therapeutic failures in superficial mycoses.

  16. Stability indicating methods for the determination of some anti-fungal agents using densitometric and RP-HPLC methods.

    PubMed

    Mousa, Bahia Abbas; El-Kousy, Naglaa Mahmoud; El-Bagary, Ramzia Ismail; Mohamed, Nashwah Gadalla

    2008-02-01

    Two chromatographic methods were developed for the determination of some anti-fungal drugs in the presence of either their degradation products or cortisone derivatives. The densitometric method determined mixtures of each of ketoconazole (KT), clotrimazole (CL), miconazole nitrate (MN) and econazole nitrate (EN) with the degradation products of each one. Mixtures of MN with hydrocortisone (HC) and of EN with triamcinolone acetonide (TA) were also successfully separated and determined by this technique. For KT and CL, a mixture of methanol:water:triethylamine (70:28:2 v/v) was used as a developing system and the spots were scanned at 243 nm and 220 nm for KT and CL, respectively. For MN and EN, a mixture of hexane:isopropyl alcohol:triethylamine (80:17:3 v/v) was used as a developing system and the spots were scanned at 225 nm for both drugs. The HPLC method determined mixtures of CL or EN with their degradation products which were separated and quantified on a Zorbax C8 column. Elution was carried out using methanol:phosphate buffer pH 2.5 (65:35 v/v) as a mobile phase at a flow rate of 1.5 ml/min and UV detection at 220 nm for CL. For EN, a mixture of methanol:water containing 0.06 ml triethylamine pH 10 (75:25 v/v) was used as a mobile phase at a flow rate of 1.5 ml/min and UV detection at 225 nm. The methods were also used to separate mixtures of CL with betamethasone dipropionate (BD) and EN with TA in a laboratory prepared mixture and in pharmaceutical preparations. The methods were sensitive, precise and applicable for determination of the drugs in pharmaceutical dosage forms.

  17. Arylimidamide-Azole Combinations Against Leishmaniasis

    DTIC Science & Technology

    2015-09-01

    micronucleus assays, drug-drug interaction studies, liver enzyme induction assays, etc. Candidate drugs that survive this testing battery are deemed...No synergy was demonstrated with azole compounds in vitro against L. major. Initial in vivo testing of these compounds using an assay to detect...enhanced the efficacy of the arylimidamide compounds. The element of work performed at WRAIR encompasses the testing of these arylimidamide analogues

  18. [Recent advances in the study of new antifungal lead compounds].

    PubMed

    Wang, Sheng-zheng; Sheng, Chun-quan; Zhang, Wan-nian

    2010-08-01

    In recent years, the incidence and mortality rate of invasive fungal infection have increased dramatically, and it is of great significance to develop novel antifungal agents with new chemical structure and new mode of action. In this review, novel antifungal lead compounds reported from 2007 to 2009 are reviewed. Moreover, their chemical structures, antifungal activities and structure-activity relationships have been summarized, which can provide useful information for future study of antifungal agents.

  19. Azole drug import into the pathogenic fungus Aspergillus fumigatus.

    PubMed

    Esquivel, Brooke D; Smith, Adam R; Zavrel, Martin; White, Theodore C

    2015-01-01

    The fungal pathogen Aspergillus fumigatus causes serious illness and often death when it invades tissues, especially in immunocompromised individuals. The azole class of drugs is the most commonly prescribed treatment for many fungal infections and acts on the ergosterol biosynthesis pathway. One common mechanism of acquired azole drug resistance in fungi is the prevention of drug accumulation to toxic levels in the cell. While drug efflux is a well-known resistance strategy, reduced azole import would be another strategy to maintain low intracellular azole levels. Recently, azole uptake in Candida albicans and other yeasts was analyzed using [(3)H]fluconazole. Defective drug import was suggested to be a potential mechanism of drug resistance in several pathogenic fungi, including Cryptococcus neoformans, Candida krusei, and Saccharomyces cerevisiae. We have adapted and developed an assay to measure azole accumulation in A. fumigatus using radioactively labeled azole drugs, based on previous work done with C. albicans. We used this assay to study the differences in azole uptake in A. fumigatus isolates under a variety of drug treatment conditions, with different morphologies and with a select mutant strain with deficiencies in the sterol uptake and biosynthesis pathway. We conclude that azole drugs are specifically selected and imported into the fungal cell by a pH- and ATP-independent facilitated diffusion mechanism, not by passive diffusion. This method of drug transport is likely to be conserved across most fungal species.

  20. Controlled nail delivery of a novel lipophilic antifungal agent using various modern drug carrier systems as well as in vitro and ex vivo model systems.

    PubMed

    Naumann, Sandy; Meyer, Jean-Philippe; Kiesow, Andreas; Mrestani, Yahya; Wohlrab, Johannes; Neubert, Reinhard H H

    2014-04-28

    The penetration behavior into human nails and animal hoof membranes of a novel antifungal agent (EV-086K) for the treatment of onychomycosis was investigated in this study. The new drug provides a high lipophilicity which is adverse for penetration into nails. Therefore, four different formulations were developed, with particular focus on a colloidal carrier system (CCS) due to its penetration enhancing properties. On the one hand, ex vivo penetration experiments on human nails were performed. Afterwards the human nail plates were cut by cryomicrotome in order to quantify the drug concentration in the dorsal, intermediate and ventral nail layer using high-performance liquid chromatography (HPLC) with UV detection. On the other hand, equine and bovine hoof membranes were used to determine the in vitro penetration of the drug into the acceptor compartment of an online diffusion cell coupled with Fourier transform infrared attenuated total reflectance (FTIR-ATR) spectroscopy. In combination, both results should exhibit a correlation between the EV-086K penetration behavior in human nail plates and animal hoof membranes. The investigations showed that the developed CCS could increase drug delivery through the human nail most compared to other formulations (nail lacquer, solution and hydrogel). Using animal hooves in the online diffusion cell, we were able to calculate pharmacokinetic data of the penetration process, especially diffusion and permeability coefficients. Finally, a qualitative correlation between the penetration results of human nails and equine hooves was established.

  1. Treating chromoblastomycosis with systemic antifungals.

    PubMed

    Bonifaz, Alexandro; Paredes-Solís, Vanessa; Saúl, Amado

    2004-02-01

    Chromoblastomycosis is a subcutaneous mycosis for which there is no treatment of choice but rather, several treatment options, with low cure rates and many relapses. The choice of treatment should consider several conditions, such as the causal agent (the most common one being Fonsecaea pedrosoi ), extension of the lesions, clinical topography and health status of the patient. Most oral and systemic antifungals have been used; the best results have been obtained with itraconazole and terbinafine at high doses, for a mean of 6 - 12 months. In extensive and refractory cases, chemotherapy with oral antifungals may be associated with thermotherapy (local heat and/or cryosurgery). Limited or early cases may be managed with surgical methods, always associated with oral antifungal agents. It is important to determine the in vitro sensitivity of the major causal agents to the various drugs, by estimating the minimum inhibitory concentration, as well as drug tolerability and drug interactions.

  2. In Vitro Susceptibility and Trailing Growth Effect of Clinical Isolates of Candida Species to Azole Drugs

    PubMed Central

    Zomorodian, Kamiar; Bandegani, Azadeh; Mirhendi, Hossein; Pakshir, Keyvan; Alinejhad, Navvab; Poostforoush Fard, Ali

    2016-01-01

    Background: Emergence of resistance to respective antifungal drugs is a primary concern for the treatment of candidiasis. Hence, determining antifungal susceptibility of the isolated yeasts is of special importance for effective therapy. For this purpose, the clinical laboratory standard institute (CLSI) has introduced a broth microdilution method to determine minimum inhibitory concentration (MIC). However, the so-called “Trailing effect” phenomenon might sometimes pose ambiguity in the interpretation of the results. Objectives: The present study aimed to determine the in vitro susceptibility of clinical isolates of Candida against azoles and the frequency of the Trailing effect. Materials and Methods: A total of 193 Candida isolates were prospectively collected and identified through the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Using a broth microdilution test, according to the guidelines of CLSI M27-A3, antifungal susceptibilities of the isolated yeasts against Fluconazole (FLU), Itraconazole (ITR), Ketoconazole (KET) and Voriconazole (VOR) were assessed. Moreover, trailing growth was determined when a susceptible MIC was incubated for 24 hours, and turned into a resistant one after 48 hours of incubation. Results: Among the tested antifungal drugs in this study, the highest rate of resistance was observed against ITR (28.5%) followed by VOR (26.4%), FLU (20.8%) and KET (1.5%). The trailing effect was induced in 27 isolates (14.0%) by VOR, in 26 isolates (13.5%) by ITR, in 24 isolates (12.4%) by FLU, and in 19 isolates (9.8%) by KET. Conclusions: The monitoring of antifungal susceptibilities of Candida species isolated from clinical sources is highly recommended for the efficient management of patients. Moreover, the trailing effect should be taken into consideration once the interpretation of the results is intended. PMID:27127587

  3. Determination of antifungal susceptibility patterns among the environmental isolates of Aspergillus fumigatus in Iran

    PubMed Central

    Mohammadi, Faezeh; Dehghan, Parvin; Nekoeian, Shahram; Hashemi, Seyed Jamal

    2016-01-01

    Background: In recent years, triazole-resistant environmental isolates of Aspergillus fumigatus have emerged in Europe and Asia. Azole resistance has been reported in patients who are treated with long-term azole therapy or exposure of the fungus spores to the azole fungicides used in agriculture. To date, a wide range of mutations in A. fumigatus have been described conferring azole-resistance, which commonly involves modifications in the cyp51A gene. We investigated antifungal susceptibility pattern of environmental isolates of A. fumigatus. Materials and Methods: In this study, 170 environmental samples collected from indoors surfaces of three hospitals in Iran. It was used β-tubulin gene to confirm the all of A. fumigatus isolates, which was identified by conventional methods. Furthermore, the antifungal susceptibility of itraconazole, voriconazole, and posaconazole was investigated using broth microdilution test, according to European Committee on Antimicrobial Susceptibility testing reference method. Results: From a total of 158 environmental molds fungi obtained from the hospitals, 58 isolates were identified as A. fumigatus by amplification of expected size of β-tubulin gene (~500 bp). In this study, in vitro antifungal susceptibility testing has shown that there were not high minimum inhibitory concentration values of triazole antifungals in all of the 58 environmental isolates of A. fumigatus. Conclusion: Our findings demonstrated that there was not azole-resistant among environmental isolates of A. fumigatus. Medical triazoles compounds have structural similarity with triazole fungicide compounds in agriculture, therefore, resistance development through exposure to triazole fungicide compounds in the environment is important but it sounds there is not a serious health problem in drug resistance in environmental isolates in Iran. PMID:27656605

  4. Posaconazole after previous antifungal therapy with voriconazole for therapy of invasive aspergillus disease, a retrospective analysis.

    PubMed

    Heinz, Werner J; Egerer, Gerlinde; Lellek, Heinrich; Boehme, Angelika; Greiner, Jochen

    2013-05-01

    Invasive aspergillosis is an important cause of morbidity and mortality in haematological patients. Current guidelines recommend voriconazole as first-line therapy. A change in class of antifungal agent is generally recommended for salvage therapy. The focus of this analysis was to assess if posaconazole is suitable for salvage therapy following voriconazole treatment. This was a retrospective investigation on patients with sequential antifungal therapy of posaconazole after voriconazole identified at four German hospitals. Response rates at 30 and 60 days following start of posaconazole application and toxicity of azoles by comparing liver enzymes and cholestasis parameters were evaluated. Data were analysed by descriptive statistics. Overall, the success rate was 72.2% [15 of 36 patients showed complete response (41.7%), 11 patients partial response (30.6%) at any time point], eight patients failed treatment and two were not evaluable. Mean laboratory values increased during voriconazole and decreased during posaconazole treatment: aspartate aminotransferase (increase: 31.9 U l(-1) vs. decrease: 19.6 U l(-1) ), alanine aminotransferase (32.4 U l(-1) vs. 19.8 U l(-1) ), gamma-glutamyl transferase (124.2 U l(-1) vs. 152.3 U l(-1) ) and alkaline phosphatase (71.5 U l(-1) vs. 40.3 U l(-1) ) respectively. No patient discontinued posaconazole therapy due to an adverse event. In this analysis posaconazole was a safe and effective antifungal salvage therapy in patients with prior administration of another triazole.

  5. Species Distribution and In Vitro Antifungal Susceptibility of Vulvovaginal Candida Isolates in China

    PubMed Central

    Wang, Feng-Juan; Zhang, Dai; Liu, Zhao-Hui; Wu, Wen-Xiang; Bai, Hui-Hui; Dong, Han-Yu

    2016-01-01

    Background: Vulvovaginal candidiasis (VVC) was a common infection associated with lifelong harassment of woman's social and sexual life. The purpose of this study was to describe the species distribution and in vitro antifungal susceptibility of Candida species (Candida spp.) isolated from patients with VVC over 8 years. Methods: Species which isolated from patients with VVC in Peking University First Hospital were identified using chromogenic culture media. Susceptibility to common antifungal agents was determined using agar diffusion method based on CLSI M44-A2 document. SPSS software (version 14.0, Inc., Chicago, IL, USA) was used for statistical analysis, involving statistical description and Chi-square test. Results: The most common strains were Candida (C.) albicans, 80.5% (n = 1775) followed by C. glabrata, 18.1% (n = 400). Nystatin exhibited excellent activity against all species (<4% resistant [R]). Resistance to azole drugs varied among different species. C. albicans: clotrimazole (3.1% R) < fluconazole (16.6% R) < itraconazole (51.5% R) < miconazole (54.0% R); C. glabrata: miconazole (25.6% R) < clotrimazole (50.5% R) < itraconazole (61.9% R) < fluconazole (73.3% R); Candida krusei: clotrimazole (0 R) < fluconazole (57.7% R) < miconazole (73.1% R) < itraconazole (83.3% R). The susceptibility of fluconazole was noticeably decreasing among all species in the study period. Conclusions: Nystatin was the optimal choice for the treatment of VVC at present. The species distribution and in vitro antifungal susceptibility of Candida spp. isolated from patients with VVC had changed over time. PMID:27174323

  6. Modern antifungal therapy for neutropenic fever.

    PubMed

    Corey, Melissa

    2006-06-01

    Empirical antifungal therapy has been shown to decrease the number of documented fungal infections in the setting of persistent fever during neutropenia. For decades, amphotericin B deoxycholate has been considered the agent of choice for first-line therapy in this setting. New antifungal agents associated with less toxicity, including the lipid formulations of amphotericin, voriconazole, and caspofungin, are now available and are considered to be suitable alternative first-line agents. In order to ensure appropriate therapy, however, the clinician must consider not only the differences between these antifungals but also patient-specific factors before initiating treatment.

  7. In Vitro Assessment of Antifungal Therapeutic Potential of Salivary Histatin-5, Two Variants of Histatin-5, and Salivary Mucin (MUC7) Domain 1

    PubMed Central

    Situ, Hongsa; Bobek, Libuse A.

    2000-01-01

    Human salivary histatin-5 (Hsn-5) is a 24-residue peptide that possesses potent antifungal activity in vitro. The MUC7 gene encodes human salivary low-molecular-weight mucin (MG2). The candidacidal activity of MUC7 domain 1 (MUC7 D1, the N-terminal 51 amino acid residues of MUC7) in vitro has also been demonstrated. In this study, we have investigated the antifungal therapeutic potential of Hsn-5, its two variants, R12I/K17N and R12I/H21L, and MUC7 D1. First, these peptides were tested for activities against different clinically important fungi. We found them to possess broad-spectrum antifungal activities; specifically, most exhibited excellent in vitro activity against eight clinically important fungal strains tested, including Candida albicans and Candida glabrata and their azole-resistant counterparts and Cryptococcus neoformans and its amphotericin B-resistant counterpart. These findings also suggest that the mechanism of action of both Hsn-5 and MUC7 D1 for these fungi is different from that of amphotericin B or azole antifungal agents. Second, we examined the stability of these peptides in whole human saliva and human serum. In saliva, the Hsn-5 variants R12I/K17N and R12I/H21L and MUC7 D1 degraded at a lower rate than Hsn-5. In human serum, MUC7 D1 was also more stable than Hsn-5; both peptides were more stable in serum than in saliva. Third, we examined the cytotoxicity of these peptides using human erythrocytes and two human cell lines (KB and HSG). No (or very low) hemolytic activity was observed with any of the four peptides, even at the highest protein concentration tested (200 μM), while amphotericin B caused 100% hemolysis at only 12.5 μM. The toxic effects of Hsn-5 and MUC7 D1 toward KB and HSG cells were also much lower than that of amphotericin B as measured by trypan blue exclusion. Together, these findings indicate that the investigated peptides possess high antifungal therapeutic potential, in particular for the treatment of drug

  8. Cross-resistance to fluconazole induced by exposure to the agricultural azole tetraconazole: an environmental resistance school?

    PubMed

    Rocha, Marcos Fábio Gadelha; Alencar, L P; Paiva, M A N; Melo, Luciana Magalhães; Bandeira, Silviane Praciano; Ponte, Y B; Sales, Jamille Alencar; Guedes, G M M; Castelo-Branco, D S C M; Bandeira, T J P G; Cordeiro, R A; Pereira-Neto, W A; Brandine, G S; Moreira, José Luciano Bezerra; Sidrim, José Júlio Costa; Brilhante, Raimunda Sâmia Nogueira

    2016-05-01

    This study aimed to investigate the influence of tetraconazole and malathion, both used in agricultural activities, on resistance to fluconazole, itraconazole and voriconazole in Candida parapsilosis ATCC 22019. The susceptibility to tetraconazole, malathion, fluconazole, itraconazole and voriconazole, through broth microdilution. Then, 12 independent replicates, were separated and exposed to four treatment groups, each one containing three replicates: G1: tetraconazole; G2: malathion; G3: fluconazole (positive control); G4: negative control. Replicates from G1, G2 and G3, were exposed to weekly increasing concentrations of tetraconazole, malathion and fluconazole, respectively, ranging from MIC/2 to 32 × MIC, throughout 7 weeks. The exposure to tetraconazole, but not malathion, decreased susceptibility to clinical azoles, especially fluconazole. The tetraconazole-induced fluconazole resistance is partially mediated by the increased activity of ATP-dependent efflux pumps, considering the increase in antifungal susceptibility after the addition of the efflux pump inhibitor, promethazine, and the increase in rhodamine 6G efflux and CDR gene expression in the G1 replicates. Moreover, MDR expression was only detected in G1 and G3 replicates, suggesting that MDR pumps are also involved in tetraconazole-induced fluconazole resistance. It is noteworthy that tetraconazole and fluconazole-treated replicates behaved similarly, therefore, resistance to azoles of clinical use may be a consequence of using azoles in farming activities.

  9. Antifungal Susceptibilities of Candida Species Causing Vulvovaginitis and Epidemiology of Recurrent Cases

    PubMed Central

    Richter, Sandra S.; Galask, Rudolph P.; Messer, Shawn A.; Hollis, Richard J.; Diekema, Daniel J.; Pfaller, Michael A.

    2005-01-01

    There are limited data regarding the antifungal susceptibility of yeast causing vulvovaginal candidiasis, since cultures are rarely performed. Susceptibility testing was performed on vaginal yeast isolates collected from January 1998 to March 2001 from 429 patients with suspected vulvovaginal candidiasis. The charts of 84 patients with multiple positive cultures were reviewed. The 593 yeast isolates were Candida albicans (n = 420), Candida glabrata (n = 112), Candida parapsilosis (n = 30), Candida krusei (n = 12), Saccharomyces cerevisiae ( n = 9), Candida tropicalis (n = 8), Candida lusitaniae (n = 1), and Trichosporon sp. (n = 1). Multiple species suggesting mixed infection were isolated from 27 cultures. Resistance to fluconazole and flucytosine was observed infrequently (3.7% and 3.0%); 16.2% of isolates were resistant to itraconazole (MIC ≥ 1 μg/ml). The four imidazoles (econazole, clotrimazole, miconazole, and ketoconazole) were active: 94.3 to 98.5% were susceptible at ≤1 μg/ml. Among different species, elevated fluconazole MICs (≥16 μg/ml) were only observed in C. glabrata (15.2% resistant [R], 51.8% susceptible-dose dependent [S-DD]), C. parapsilosis (3.3% S-DD), S. cerevisiae (11.1% S-DD), and C. krusei (50% S-DD, 41.7% R, considered intrinsically fluconazole resistant). Resistance to itraconazole was observed among C. glabrata (74.1%), C. krusei (58.3%), S. cerevisiae (55.6%), and C. parapsilosis (3.4%). Among 84 patients with recurrent episodes, non-albicans species were more common (42% versus 20%). A ≥4-fold rise in fluconazole MIC was observed in only one patient with C. parapsilosis. These results support the use of azoles for empirical therapy of uncomplicated candidal vulvovaginitis. Recurrent episodes are more often caused by non-albicans species, for which azole agents are less likely to be effective. PMID:15872235

  10. Antifungal agent susceptibilities and interpretation of Malassezia pachydermatis and Candida parapsilosis isolated from dogs with and without seborrheic dermatitis skin.

    PubMed

    Yurayart, Chompoonek; Nuchnoul, Noppawan; Moolkum, Pornsawan; Jirasuksiri, Supitcha; Niyomtham, Waree; Chindamporn, Ariya; Kajiwara, Susumu; Prapasarakul, Nuvee

    2013-10-01

    Malassezia pachydermatis and Candida parapsilosis are recognized as commensal yeasts on the skin of healthy dogs but also causative agents of eborrheic dermatitis, especially in atopic dogs. We determined and compared the susceptibility levels of yeasts isolated from dogs with and without seborrheic dermatitis (SD) using the disk diffusion method (DD) for itraconazole (ITZ), ketoconazole (KTZ), nystatin (NYS), terbinafine (TERB) and 5-fluorocytosine (5-FC) and the broth microdilution method (BMD) for ITZ and KTZ. The reliability between the methods was assessed using an agreement analysis and linear regression. Forty-five M. pachydermatis and 28 C. parapsilosis isolates were identified based on physiological characteristics and an approved molecular analysis. By DD, all tested M. pachydermatis isolates were susceptible to ITZ, KTZ, NYS and TERB but resistant to 5-FC. Only 46 - 60% of the tested C. parapsilosis isolates were susceptible to KTZ, TERB and 5-FC, but ITZ and NYS were effective against all. By BMD, over 95% of M. pachydermatis isolates were susceptible to KTZ and ITZ with an MIC90 < 0.03 and 0.12 μg/ml, respectively. The frequency of KTZ- and ITZ-resistant C. parapsilosis was 29% and 7%, and the MIC90 values were 1 μg/ml and 0.5-1 μg/ml, respectively. Regarding the agreement analysis, 2.2% of minor errors were observed in M. pachydermatis and 0.2-1% of very major errors occurred among C. parapsilosis. There were no significant differences in the yeast resistance rates between dogs with and without SD. KTZ and ITZ were still efficacious for M. pachydermatis but a high rate of KTZ resistant was reported in C. parapsilosis.

  11. Multilocus resistance evolution to azole fungicides in fungal plant pathogen populations.

    PubMed

    Mohd-Assaad, Norfarhan; McDonald, Bruce A; Croll, Daniel

    2016-12-01

    Evolution of fungicide resistance is a major threat to food production in agricultural ecosystems. Fungal pathogens rapidly evolved resistance to all classes of fungicides applied to the field. Resistance to the commonly used azole fungicides is thought to be driven mainly by mutations in a gene (CYP51) encoding a protein of the ergosterol biosynthesis pathway. However, some fungi gained azole resistance independently of CYP51 mutations and the mechanisms leading to CYP51-independent resistance are poorly understood. We used whole-genome sequencing and genome-wide association studies (GWAS) to perform an unbiased screen of azole resistance loci in Rhynchosporium commune, the causal agent of the barley scald disease. We assayed cyproconazole resistance in 120 isolates collected from nine populations worldwide. We found that mutations in highly conserved genes encoding the vacuolar cation channel YVC1, a transcription activator, and a saccharopine dehydrogenase made significant contributions to fungicide resistance. These three genes were not previously known to confer resistance in plant pathogens. However, YVC1 is involved in a conserved stress response pathway known to respond to azoles in human pathogenic fungi. We also performed GWAS to identify genetic polymorphism linked to fungal growth rates. We found that loci conferring increased fungicide resistance were negatively impacting growth rates, suggesting that fungicide resistance evolution imposed costs. Analyses of population structure showed that resistance mutations were likely introduced into local populations through gene flow. Multilocus resistance evolution to fungicides shows how pathogen populations can evolve a complex genetic architecture for an important phenotypic trait within a short time span.

  12. [Pharmacology of the antifungals used in the treatment of aspergillosis].

    PubMed

    Azanza, José Ramón; Sádaba, Belén; Gómez-Guíu, Almudena

    2014-01-01

    The treatment of invasive aspergillosis requires the use of drugs that characteristically have complex pharmacokinetic properties, the knowledge of which is essential to achieve maximum efficacy with minimal risk to the patient. The lipid-based amphotericin B formulations vary significantly in their pharmacokinetic behaviour, with very high plasma concentrations of the liposomal form, probably related to the presence of cholesterol in their structure. Azoles have a variable absorption profile, particularly in the case of itraconazole and posaconazole, with the latter very dependent on multiple factors. This may also lead to variations in voriconazole, which requires considering the possibility of monitoring plasma concentrations. The aim of this article is to review some of the most relevant aspects of the pharmacology of the antifungals used in the prophylaxis and treatment of the Aspergillus infection. For this reason, it includes the most relevant features of some of the azoles normally prescribed in this infection (itraconazole, posaconazole and voriconazole) and the amphotericin B formulations.

  13. Antifungal Lock Therapy

    PubMed Central

    Walraven, Carla J.

    2013-01-01

    The widespread use of intravascular devices, such as central venous and hemodialysis catheters, in the past 2 decades has paralleled the increasing incidence of catheter-related bloodstream infections (CR-BSIs). Candida albicans is the fourth leading cause of hospital-associated BSIs. The propensity of C. albicans to form biofilms on these catheters has made these infections difficult to treat due to multiple factors, including increased resistance to antifungal agents. Thus, curing CR-BSIs caused by Candida species usually requires catheter removal in addition to systemic antifungal therapy. Alternatively, antimicrobial lock therapy has received significant interest and shown promise as a strategy to treat CR-BSIs due to Candida species. The existing in vitro, animal, and patient data for treatment of Candida-related CR-BSIs are reviewed. The most promising antifungal lock therapy (AfLT) strategies include use of amphotericin, ethanol, or echinocandins. Clinical trials are needed to further define the safety and efficacy of AfLT. PMID:23070153

  14. Antifungal prophylaxis during neutropenia and immunodeficiency.

    PubMed Central

    Lortholary, O; Dupont, B

    1997-01-01

    Fungal infections represent a major source of morbidity and mortality in patients with almost all types of immunodeficiencies. These infections may be nosocomial (aspergillosis) or community acquired (cryptococcosis), or both (candidiasis). Endemic mycoses such as histoplasmosis, coccidioidomycosis, and penicilliosis may infect many immunocompromised hosts in some geographic areas and thereby create major public health problems. With the wide availability of oral azoles, antifungal prophylactic strategies have been extensively developed. However, only a few well-designed studies involving strict criteria have been performed, mostly in patients with hematological malignancies or AIDS. In these situations, the best dose and duration of administration of the antifungal drug often remain to be determined. In high-risk neutropenic or bone marrow transplant patients, fluconazole is effective for the prevention of superficial and/or systemic candidal infections but is not always able to prolong overall survival and potentially selects less susceptible or resistant Candida spp. Primary prophylaxis against aspergillosis remains investigative. At present, no standard general recommendation for primary antifungal prophylaxis can be proposed for AIDS patients or transplant recipients. However, for persistently immunocompromised patients who previously experienced a noncandidal systemic fungal infection, prolonged suppressive antifungal therapy is often indicated to prevent a relapse. Better strategies for controlling immune deficiencies should also help to avoid some potentially life-threatening deep mycoses. When prescribing antifungal prophylaxis, physicians should be aware of the potential emergence of resistant strains, drug-drug interactions, and the cost. Well-designed, randomized, multicenter clinical trials in high-risk immunocompromised hosts are urgently needed to better define how to prevent severe invasive mycoses. PMID:9227863

  15. Synthesis and structure-activity relationships of 2-phenyl-1-[(pyridinyl- and piperidinylmethyl)amino]-3-(1H-1,2,4-triazol-1-yl)propan-2-ols as antifungal agents.

    PubMed

    Giraud, Francis; Guillon, Rémi; Logé, Cédric; Pagniez, Fabrice; Picot, Carine; Le Borgne, Marc; Le Pape, Patrice

    2009-01-15

    Continuous efforts on the synthesis and structure-activity relationships (SARs) studies of modified 1-benzylamino-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propan-2-ols as antifungal agents, allowed identification of new 1-[(pyridinyl- and piperidinylmethyl)amino] derivatives with MIC(80) values ranging from 1410.0 to 23.0ngmL(-1) on Candidaalbicans. These results confirmed both the importance of pi-pi stacking and hydrogen bonding interactions in the active site of CYP51-C. albicans.

  16. A Novel Zn2-Cys6 Transcription Factor AtrR Plays a Key Role in an Azole Resistance Mechanism of Aspergillus fumigatus by Co-regulating cyp51A and cdr1B Expressions

    PubMed Central

    Shimizu, Kiminori; Paul, Sanjoy; Ohba, Ayumi; Gonoi, Tohru; Watanabe, Akira; Gomi, Katsuya

    2017-01-01

    Successful treatment of aspergillosis caused by Aspergillus fumigatus is threatened by an increasing incidence of drug resistance. This situation is further complicated by the finding that strains resistant to azoles, the major antifungal drugs for aspergillosis, have been widely disseminated across the globe. To elucidate mechanisms underlying azole resistance, we identified a novel transcription factor that is required for normal azole resistance in Aspergillus fungi including A. fumigatus, Aspergillus oryzae, and Aspergillus nidulans. This fungal-specific Zn2-Cys6 type transcription factor AtrR was found to regulate expression of the genes related to ergosterol biosynthesis, including cyp51A that encodes a target protein of azoles. The atrR deletion mutant showed impaired growth under hypoxic conditions and attenuation of virulence in murine infection model for aspergillosis. These results were similar to the phenotypes for a mutant strain lacking SrbA that is also a direct regulator for the cyp51A gene. Notably, AtrR was responsible for the expression of cdr1B that encodes an ABC transporter related to azole resistance, whereas SrbA was not involved in the regulation. Chromatin immunoprecipitation assays indicated that AtrR directly bound both the cyp51A and cdr1B promoters. In the clinically isolated itraconazole resistant strain that harbors a mutant Cyp51A (G54E), deletion of the atrR gene resulted in a hypersensitivity to the azole drugs. Together, our results revealed that AtrR plays a pivotal role in a novel azole resistance mechanism by co-regulating the drug target (Cyp51A) and putative drug efflux pump (Cdr1B). PMID:28052140

  17. Reactivity of azole anions with CO₂ from the DFT perspective.

    PubMed

    Tang, Huarong; Wu, Chao

    2013-06-01

    Azole anions are key components in CO₂ capture materials that include ionic liquids and porous solids. Herein, we use density functional theory (DFT) and a Langmuir-type adsorption model to study azole anion-CO₂ interactions. Linear CO₂ has to be bent by approximately 45° to form an N-C bond within the azole ring. The energy cost of bending renders CO₂ absorption much more difficult compared to SO₂ absorption. For different azole anions, the number of nitrogen atoms in the ring and the natural bond orbital energy of the reacting nitrogen lone pair, both linearly correlate with the calculated reaction enthalpy and are useful handles for new sorbent designs. Unlike for SO₂, the azole parent architecture (unsubstituted) does not allow successive CO₂ absorption under mild conditions (<0.12 MPa and at room temperature). Experimental CO₂ and SO₂ absorption isotherms are reproduced by using the Langmuir model parameterized with the calibrated DFT reaction enthalpies. This study provides insight for designing azole-based CO₂-capture materials.

  18. Antifungal Prophylaxis in Immunocompromised Patients

    PubMed Central

    Vazquez, Lourdes

    2016-01-01

    Invasive fungal infections (IFIs) represent significant complications in patients with hematological malignancies. Chemoprevention of IFIs may be important in this setting, but most antifungal drugs have demonstrated poor efficacy, particularly in the prevention of invasive aspergillosis. Antifungal prophylaxis in hematological patients is currently regarded as the gold standard in situations with a high risk of infection, such as acute leukemia, myelodysplastic syndromes, and autologous or allogeneic hematopoietic stem cell transplantation. Over the years, various scientific societies have established a series of recommendations for antifungal prophylaxis based on prospective studies performed with different drugs. However, the prescription of each agent must be personalized, adapting its administration to the characteristics of individual patients and taking into account possible interactions with concomitant medication. PMID:27648203

  19. Treatment of invasive fungal infections in high risk hematological patients. The outcome with liposomal amphotericin B is not negatively affected by prior administration of mold-active azoles.

    PubMed

    De la Serna, Javier; Jarque, Isidro; López-Jiménez, Javier; Fernández-Navarro, Jose María; Gómez, Valle; Jurado, Manuel; Pascual, Adriana; Serrano, Josefina; Romero, Mónica; Vallejo, Carlos

    2013-03-01

    There are concerns of a reduced effect of liposomal amphotericin B (L-AmB) given sequentially after mold-active azoles due to a possible antagonism in their antifungal mechanism. To investigate this possible effect in the clinic, we retrospectively studied 182 high risk hematologic patients with invasive fungal infections (IFI) who were treated with L-AmB. Overall, 96 patients (52.7%) had possible, 52 (28.6%) probable and 34 (18.7%) proven IFI according to EORTC classification. Most had suspected or proven invasive aspergillosis. We compared patients with prior exposure to mold-active azoles (n=100) to those having not (n=82). The group with prior mold-active azoles included more patients with poor risk features for IFI as acute myeloid leukemia (p<0.05) and prolonged neutropenia (p<0.05). A favorable response in the IFI, defined as a complete or partial response, was achieved in 75% and 74.4% of patients in the whole cohort, and in 66% and 74.4% of patients with probable or proven IFI in the two groups. None of these differences were significant. Multivariate analysis showed that refractory baseline disease and renal dysfunction were adverse factors for response in the IFI (p<0.05). Survival was poorer for patients with prior broad spectrum azoles (p<0.05), and for those who did not recover from neutropenia (p<0.05). In conclusion, the effectiveness of treatment of breakthrough fungal infection with L-AmB is not likely to be affected by prior exposure to mold-active azoles prophylaxis, but survival largely depends on host and disease factors.

  20. Acquired Multidrug Antifungal Resistance in Candida lusitaniae during Therapy

    PubMed Central

    Asner, Sandra A.; Giulieri, Stefano; Diezi, Manuel; Marchetti, Oscar

    2015-01-01

    Candida lusitaniae is usually susceptible to echinocandins. Beta-1,3-glucan synthase encoded by FKS genes is the target of echinocandins. A few missense mutations in the C. lusitaniae FKS1 hot spot 1 (HS1) have been reported. We report here the rapid emergence of antifungal resistance in C. lusitaniae isolated during therapy with amphotericin B (AMB), caspofungin (CAS), and azoles for treatment of persistent candidemia in an immunocompromised child with severe enterocolitis and visceral adenoviral disease. As documented from restriction fragment length polymorphism (RFLP) and random amplified polymorphic DNA (RAPD) analysis, the five C. lusitaniae isolates examined were related to each other. From antifungal susceptibility and molecular analyses, 5 different profiles (P) were obtained. These profiles included the following: profile 1 (P1) (CAS MIC [μg/ml], 0.5; fluconazole [FLC] MIC, 0.25), determined while the patient was being treated with liposomal AMB for 3 months; P2 (FLC MIC [μg/ml], 0.25; CAS MIC, 4), while the patient was being treated with CAS for 2 weeks; P3 (CAS MIC [μg/ml], 0.5; FLC MIC, 32), while the patient was being treated with azoles and CAS initially followed by azoles alone for a week; P4 (CAS MIC [μg/ml], 8; FLC MIC, 8), while the patient was being treated with both drugs for 3 weeks; and P5 (AMB MIC [μg/ml], 0.125; CAS MIC, 8), while the patient was being treated with AMB and FLC for 2 weeks. CAS resistance was associated with resistance not only to micafungin and anidulafungin but also to AMB. Analysis of CAS resistance revealed 3 novel FKS1 mutations in CAS-resistant isolates (S638Y in P2; S631Y in P4; S638P in P5). While S638Y and -P are within HS1, S631Y is in close proximity to this domain but was confirmed to confer candin resistance using a site-directed mutagenesis approach. FLC resistance could be linked with overexpression of major facilitator gene 7 (MFS7) in C. lusitaniae P2 and P4 and was associated with resistance to 5

  1. Antifungal Activity of C-27 Steroidal Saponins

    PubMed Central

    Yang, Chong-Ren; Zhang, Ying; Jacob, Melissa R.; Khan, Shabana I.; Zhang, Ying-Jun; Li, Xing-Cong

    2006-01-01

    As part of our search for new antifungal agents from natural resources, 22 C-27 steroidal saponins and 6 steroidal sapogenins isolated from several monocotyledonous plants were tested for their antifungal activity against the opportunistic pathogens Candida albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, and Aspergillus fumigatus. The results showed that the antifungal activity of the steroidal saponins was associated with their aglycone moieties and the number and structure of monosaccharide units in their sugar chains. Within the 10 active saponins, four tigogenin saponins (compounds 1 to 4) with a sugar moiety of four or five monosaccharide units exhibited significant activity against C. neoformans and A. fumigatus, comparable to the positive control amphotericin B. The antifungal potency of these compounds was not associated with cytotoxicity to mammalian cells. This suggests that the C-27 steroidal saponins may be considered potential antifungal leads for further preclinical study. PMID:16641439

  2. Aspergillus tanneri sp. nov., a New Pathogen That Causes Invasive Disease Refractory to Antifungal Therapy

    PubMed Central

    Sugui, Janyce A.; Peterson, Stephen W.; Clark, Lily P.; Nardone, Glenn; Folio, Les; Riedlinger, Gregory; Zerbe, Christa S.; Shea, Yvonne; Henderson, Christina M.; Zelazny, Adrian M.; Holland, Steven M.

    2012-01-01

    The most common cause of invasive aspergillosis (IA) in patients with chronic granulomatous disease (CGD) is Aspergillus fumigatus followed by A. nidulans; other aspergilli rarely cause the disease. Here we review two clinical cases of fatal IA in CGD patients and describe a new etiologic agent of IA refractory to antifungal therapy. Unlike typical IA caused by A. fumigatus, the disease caused by the new species was chronic and spread from the lung to multiple adjacent organs. Mycological characteristics and the phylogenetic relationship with other aspergilli based on the sequence analysis of Mcm7, RPB2, and Tsr1 indicated that the new species, which we named as A. tanneri, belongs to Aspergillus section Circumdati. The species has a higher amphotericin B, voriconazole, and itraconazole MIC and causes more chronic infection in CGD mice than A. fumigatus. This is the first report documenting IA in CGD patients caused by a species belonging to the Aspergillus section Circumdati that is inherently resistant to azoles and amphotericin B. Unlike the results seen with many members of Aspergillus section Circumdati, ochratoxin was not detected in filtrates of cultures grown in various media. Our phenotypic and genetic characterization of the new species and the case reports will assist future diagnosis of infection caused by A. tanneri and lead to more appropriate patient management. PMID:22855513

  3. Epidemiology and antifungal susceptibilities of yeasts causing vulvovaginitis in a teaching hospital.

    PubMed

    Gamarra, Soledad; Morano, Susana; Dudiuk, Catiana; Mancilla, Estefanía; Nardin, María Elena; de Los Angeles Méndez, Emilce; Garcia-Effron, Guillermo

    2014-10-01

    Vulvovaginal candidiasis is one of the most common mycosis. However, the information about antifungal susceptibilities of the yeasts causing this infection is scant. We studied 121 yeasts isolated from 118 patients with vulvovaginal candidiasis. The isolates were identified by phenotypic and molecular methods, including four phenotypic methods described to differentiate Candida albicans from C. dubliniensis. Antifungal susceptibility testing was performed according to CLSI documents M27A3 and M27S4 using the drugs available as treatment option in the hospital. Diabetes, any antibacterial and amoxicillin treatment were statistically linked with vulvovaginal candidiasis, while oral contraceptives were not considered a risk factor. Previous azole-based over-the-counter antifungal treatment was statistically associated with non-C.albicans yeasts infections. The most common isolated yeast species was C. albicans (85.2 %) followed by C. glabrata (5 %), Saccharomyces cerevisiae (3.3 %), and C. dubliniensis (2.5 %). Fluconazole- and itraconazole-reduced susceptibility was observed in ten and in only one C. albicans strains, respectively. All the C. glabrata isolates showed low fluconazole MICs. Clotrimazole showed excellent potency against all but seven isolates (three C. glabrata, two S. cerevisiae, one C. albicans and one Picchia anomala). Any of the strains showed nystatin reduced susceptibility. On the other hand, terbinafine was the less potent drug. Antifungal resistance is still a rare phenomenon supporting the use of azole antifungals as empirical treatment of vulvovaginal candidiasis.

  4. Efficient Production of the Flavoring Agent Zingerone and of both (R)- and (S)-Zingerols via Green Fungal Biocatalysis. Comparative Antifungal Activities between Enantiomers

    PubMed Central

    Svetaz, Laura A.; Di Liberto, Melina G.; Zanardi, María M.; Suárez, Alejandra G.; Zacchino, Susana A.

    2014-01-01

    Zingerone (1) and both chiral forms of zingerol (2) were obtained from dehydrozingerone (3) by biotransformation with filamentous fungi. The bioconversion of 3 with A. fumigatus, G. candidum or R. oryzae allowed the production of 1 as the sole product at 8 h and in 81%–90% at 72 h. In turn, A. flavus, A. niger, C. echinulata, M. circinelloides and P. citrinum produced 1 at 8 h, but at 72 h alcohol 2 was obtained as the major product (74%–99%). Among them, A. niger and M. circinelloides led to the anti-Prelog zingerol (R)-2 in only one step with high conversion rates and ee. Instead, C. echinulata and P. citrinum allowed to obtain (S)-2 in only one step, with high conversion rates and ee. Both chiral forms of 2 were tested for antifungal properties against a panel of clinically important fungi, showing that (R)-, but not (S)-2 possessed antifungal activity. PMID:25470023

  5. An alternative anionic bio-sustainable anti-fungal agent: Investigation of its mode of action on the fungal cell membrane.

    PubMed

    Stenbæk, Jonas; Löf, David; Falkman, Peter; Jensen, Bo; Cárdenas, Marité

    2017-07-01

    The potential of a lactylate (the sodium caproyl lactylate or C10 lactylate), a typical food grade emulsifier, as an anionic environmental friendly anti-fungal additive was tested in growth medium and formulated in a protective coating for exterior wood. Different laboratory growth tests on the blue stain fungus Aureobasidium pullulans were performed and its interactions on a model fungal cell membrane were studied. Promising short term anti-fungal effects in growth tests were observed, although significant but less dramatic effects took place in coating test on wood panels. Scanning electron microscope analysis shows clear differences in the amount of fungal slime on the mycelium of Aureobasidium pullulans when the fungus was exposed of C10 lactylate. This could indicate an effect on the pullulan and melanin production by the fungus. Moreover, the interaction studies on model fungal cell membranes show that C10 lactylate affects the phospholipid bilayer in a similar manner to other negative charged detergents.

  6. Empirical antifungal therapy in patients with neutropenia and persistent or recurrent fever of unknown origin.

    PubMed

    Martino, Rodrigo; Viscoli, Claudio

    2006-01-01

    Persistent or recurrent fever of unexplained origin (PFUO) in neutropenic patients receiving antibiotic therapy is commonly treated with empirical antifungal therapy (EAFT). EAFT was established as an adequate management of PFUO around 20 years ago with conventional amphotericin B deoxycholate (c-AmB), despite its high rate of infusional and systemic toxicities. In recent years, EAFT trials for PFUO have used less toxic agents, such as the lipid formulations of AmB, the new azoles, and the echinocandin, caspofungin. In clinical trials, the lipid formulations of AmB [especially liposomal AmB (L-AmB)] provided similar efficacy with lower toxicity but at a much higher cost. Although rarely used in clinical practice, fluconazole is equivalent to c-AmB, provided patients at high risk of Aspergillus infections are excluded. Intravenous itraconazole was shown to be equivalent to c-AmB, with a lower toxicity. Voriconazole did not meet non-inferiority criteria when compared with L-AmB. Caspofungin was shown to be non-inferior to L-AmB and more effective in treating baseline invasive fungal infections. To date, alternatives to AmB have shown less toxicity, but improved efficacy is less clear. This is probably because of the weakness of the indication and to the consequent difficulty in establishing objective and reproducible endpoints for comparisons. The new challenge for physicians in this field is probably presumptive antifungal therapy, an approach based on patient risk-group stratification for developing invasive candidiasis or aspergillosis and/or the use of new diagnostic techniques to identify patients at a very early stage of infection.

  7. Complex mechanism of relaxation in solid chloroxylenol (antibacterial/antifungal agent) studied by ¹H NMR spectroscopy and density functional theory calculations.

    PubMed

    Latosińska, Jolanta Natalia; Latosińska, Magdalena; Tomczak, Marzena Agnieszka; Medycki, Wojciech

    2014-03-27

    Molecular relaxation in antibacterial/antifungal agent: chloroxylenol (4-chloro-3,5-dimethylphenol, PCMX) in the solid state was studied by the (1)H NMR and quantum chemistry calculations. The temperature dependencies of the proton spin-lattice relaxation time (T1) in the ranges 15-273 K (at 24.667 MHz), 77-295 K (at 15 MHz), and 112-291 K at 90 MHz and the second moment (M2) of (1)H NMR resonant line in the range 106-380 K were measured. The two minima in the temperature dependence of T1 revealed two activation processes, whereas the M2 dependence in the studied range was quite flat and revealed the only significant reduction at 380 K. The low temperature part of T1(T) dependence indicated the occurrence of two processes characteristic of methyl bearing solids; the quantum mechanics governed incoherent tunneling (responsible for the low temperature flattening of T1) and the classical Arrhenius dependence governed hindered rotation (related to the wide low temperature minimum of 0.066 s at 57 K, 24.667 MHz). The 2D potential energy surface obtained using DFT/B3LYP/6-311++G(2d,p) calculations revealed the inequivalence of methyl groups and the lack of their interplay/coupling. The activation energies of classical hindered rotation are 3.35 and 2.5 kJ/mol, whereas temperatures at which the proton tunneling T(tun) finally ceases are 52 and 63 K, for inequivalent methyl groups. C(p)(T) required for the estimation of T(tun) was calculated purely theoretically on the basis of the Einstein and Debye models of specific heat and 51 modes of atomic vibrations, 4 internal rotations, and 3 torsions calculated by DFT. The -CH3 motion (tunneling and classical) results in the reduction in the (1)H NMR line second moment from 17.3 G(2) (rigid) to approximately 11.05 G(2). The pointed high temperature minimum T1(T) of 0.109 s at 89 K, 24.667 MHz, which shifts with frequency, was assigned to small-angle libration jumps, by the Θ2 = ±15° between two positions of equilibrium. The

  8. HPLC-DAD for the determination of three different classes of antifungals: method characterization, statistical approach, and application to a permeation study.

    PubMed

    Miron, Diogo; Lange, Alini; Zimmer, Aline R; Mayorga, Paulo; Schapoval, Elfrides E S

    2014-12-01

    This study describes and characterizes methods for high-performance liquid chromatography diode array detection (HPLC-DAD) analysis of formulations containing molecules with antifungal activity of three different classes: terbinafine and butenafine (allylamines), miconazole and fluconazole (azoles), and geraniol, neral and geranial (monoterpenes). All methods used the same chromatographic column (RP18 ), enabling the analysis to be performed in a single batch. The specificity was extensively discussed through the establishment of purity peak methods. The analytical parameters (linearity, precision and accuracy) were calculated and discussed in detail using specific statistical approaches. All substances showed satisfactory results for chromatographic and analytical parameters. Limits of 1.3% to mean repeatability and 2.0% for intermediate precision are suggested as acceptance criteria in validation of methods by HPLC-DAD, in situations where there is no extensive pretreatment of the samples. The methods proved to be robust and significant factors were discussed regarding their influence on chromatographic parameters (retention time, resolution, tailing factor and column efficiency). Finally, the application of the developed methods was demonstrated by the results of a permeation study of the antifungal agents through bovine hoof membranes.

  9. The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis.

    PubMed

    Koselny, Kristy; Green, Julianne; DiDone, Louis; Halterman, Justin P; Fothergill, Annette W; Wiederhold, Nathan P; Patterson, Thomas F; Cushion, Melanie T; Rappelye, Chad; Wellington, Melanie; Krysan, Damian J

    2016-12-01

    Only one new class of antifungal drugs has been introduced into clinical practice in the last 30 years, and thus the identification of small molecules with novel mechanisms of action is an important goal of current anti-infective research. Here, we describe the characterization of the spectrum of in vitro activity and in vivo activity of AR-12, a celecoxib derivative which has been tested in a phase I clinical trial as an anticancer agent. AR-12 inhibits fungal acetyl coenzyme A (acetyl-CoA) synthetase in vitro and is fungicidal at concentrations similar to those achieved in human plasma. AR-12 has a broad spectrum of activity, including activity against yeasts (e.g., Candida albicans, non-albicans Candida spp., Cryptococcus neoformans), molds (e.g., Fusarium, Mucor), and dimorphic fungi (Blastomyces, Histoplasma, and Coccidioides) with MICs of 2 to 4 μg/ml. AR-12 is also active against azole- and echinocandin-resistant Candida isolates, and subinhibitory AR-12 concentrations increase the susceptibility of fluconazole- and echinocandin-resistant Candida isolates. Finally, AR-12 also increases the activity of fluconazole in a murine model of cryptococcosis. Taken together, these data indicate that AR-12 represents a promising class of small molecules with broad-spectrum antifungal activity.

  10. Fusarium keratitis in South India: causative agents, their antifungal susceptibilities and a rapid identification method for the Fusarium solani species complex.

    PubMed

    Homa, Mónika; Shobana, Coimbatore S; Singh, Yendrembam R B; Manikandan, Palanisamy; Selvam, Kanesan P; Kredics, László; Narendran, Venkatapathy; Vágvölgyi, Csaba; Galgóczy, László

    2013-09-01

    Seventy Fusarium isolates derived from human keratomycosis were identified based on partial sequences of the β-tubulin (β-TUB) and translation elongation factor 1α (EF-1α) genes. Most of the isolates were confirmed as members of the F. solani species complex (75.71%), followed by the F. dimerum species complex (8.57%), the F. fujikuroi species complex (8.57%), the F. oxysporum species complex (4.29%) and the F. incarnatum-equiseti species complex (2.86%). A combined phylogenetic tree was estimated including all the 70 isolates. Isolates belonging to different species complexes formed separate clades. In this study, we also report the first isolation of F. napiforme from human keratomycosis. A new method based on a specific EcoRI restriction site in the EF-1α gene was developed for the rapid identification of F. solani. In vitro antifungal susceptibilities of the isolates to seven antifungals were determined by broth microdilution method. Terbinafine, natamycin and amphotericin B proved to be the most effective drugs, followed by voriconazole. The minimal inhibitory concentrations of clotrimazole, econazole and itraconazole were generally high (≥64 μg ml(-1) ). The interactions between the two most effective antifungals (natamycin and terbinafine) were determined by checkerboard microdilution method. Synergism (71.8%) or no interaction (28.2%) was revealed between the two compounds.

  11. Exploring the molecular basis of antifungal synergies using genome-wide approaches

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This is a review article summarizing genomic profiling strategies for determining the mechanism of action of antifungal synergies, and highlighting the potential applications of these technologies. Given the limitations of currently available antifungal agents and the development of drug resistance...

  12. Species Distribution and In Vitro Azole Susceptibility of Aspergillus Section Nigri Isolates from Clinical and Environmental Settings

    PubMed Central

    Iatta, Roberta; Nuccio, Federica; Immediato, Davide; Mosca, Adriana; De Carlo, Carmela; Miragliotta, Giuseppe; Parisi, Antonio; Crescenzo, Giuseppe; Otranto, Domenico

    2016-01-01

    Aspergillus section Nigri includes species of interest for animal and human health, although studies on species distribution are limited to human cases. Data on the antifungal susceptibilities and the molecular mechanism of triazole resistance in strains belonging to this section are scant. Forty-two black Aspergillus strains from human patients (16 isolates), animals (14 isolates), and the environment (12 isolates) were molecularly characterized and their in vitro triazole susceptibilities investigated. Aspergillus tubingensis was isolated from humans, animals, and environmental settings, whereas Aspergillus awamori and Aspergillus niger were isolated exclusively from humans. Phylogenetic analyses of β-tubulin and calmodulin gene sequences were concordant in differentiating A. tubingensis from A. awamori and A. niger. Voriconazole and posaconazole (PSZ) were the most active triazoles. One A. tubingensis strain was resistant to itraconazole and PSZ and one A. niger strain to PSZ. Sequence analysis of the cyp51A gene revealed different sequence types within a species, and A. tubingensis strains were also phylogenetically distinct from A. awamori/A. niger strains according to the strain origin and susceptibility profile. Genetic analysis of the cyp51A sequences suggests that two nonsynonymous mutations resulting in amino acid substitutions in the CYP51A protein (changes of L to R at position 21 [L21R] and of Q to R at position 228 [Q228R]) might be involved in azole resistance. Though azole resistance in black Aspergillus isolates from animals and rural environments does not represent a threat to public health in Southern Italy, the use of triazoles in the clinical setting needs to better monitored. The cyp51A sequence is useful for the molecular identification of black Aspergillus, and point mutations in protein sequences could be responsible for azole resistance phenomena. PMID:27413191

  13. PilG is Involved in the Regulation of Twitching Motility and Antifungal Antibiotic Biosynthesis in the Biological Control Agent Lysobacter enzymogenes.

    PubMed

    Zhou, Xue; Qian, Guoliang; Chen, Yuan; Du, Liangcheng; Liu, Fengquan; Yuen, Gary Y

    2015-10-01

    Lysobacter enzymogenes strain C3 is a gliding bacterium which produces the antifungal secondary metabolite heat-stable antifungal factor (HSAF) and type IV pilus (T4P) as important mechanisms in biological control activity against fungal pathogens. To date, the regulators that control HSAF biosynthesis and T4P-dependent twitching motility in L. enzymogenes are poorly explored. In the present study, we addressed the role of pilG in the regulation of these two traits in L. enzymogenes. PilG of L. enzymogenes was found to be a response regulator, commonly known as a component of a two-component transduction system. Mutation of pilG in strain C3 abolished its ability to display spreading colony phenotype and cell movement at the colony margin, which is indicative of twitching motility; hence, PilG positively regulates twitching motility in L. enzymogenes. Mutation of pilG also enhanced HSAF production and the transcription of its key biosynthetic gene hsaf pks/nrps, suggesting that PilG plays a negative regulatory role in HSAF biosynthesis. This finding represents the first demonstration of the regulator PilG having a role in secondary metabolite biosynthesis in bacteria. Collectively, our results suggest that key ecological functions (HSAF production and twitching motility) in L. enzymogenes strain C3 are regulated in opposite directions by the same regulatory protein, PilG.

  14. The role of new eudesmane-type sesquiterpenoid and known eudesmane derivatives from the red alga Laurencia obtusa as potential antifungal-antitumour agents.

    PubMed

    Alarif, Walied M; Al-Footy, Khalid O; Zubair, Muhammad Sulaiman; Halid Ph, Mohamed; Ghandourah, Mohamed A; Basaif, Salim A; Al-Lihaibi, Sultan S; Ayyad, Seif-Eldin N; Badria, Farid A

    2016-01-01

    A new eudesmane sesquiterpenoid, eudesma-4(15),7-diene-5,11-diol (1) along with the known trinor-sesquiterene, teuhetenone (2), and a seco-eudesmane sesquiterpene, chabrolidione B (3), have been isolated from the Red Sea red alga Laurencia obtusa. The chemical structures were elucidated on the basis of extensive spectroscopic analysis. The antifungal and cytotoxic activities of the isolated metabolites were tested against several fungi, yeast and human mammary carcinoma cell line (MCF-7). Compounds 1 and 3 showed a much better activity [minimum inhibitory concentration (MIC): 2.9 μM] than that of amphotericin B (MIC: 4.6 μM). Interestingly, compound 2, the least active antifungal compound, retained the high anticancer activity against MCF-7 (22 μM) in comparison with cisplatin (59 μM), which was determined by employing lactate dehydrogenase assay. Compounds 1-3 are recorded here for the first time from algal flora. The chemotaxonomic importance of the isolated metabolites was discussed.

  15. Time-Kill Kinetics and In Vitro Antifungal Susceptibility of Non-fumigatus Aspergillus Species Isolated from Patients with Ocular Mycoses.

    PubMed

    Öz, Yasemin; Özdemir, Havva Gül; Gökbolat, Egemen; Kiraz, Nuri; Ilkit, Macit; Seyedmousavi, Seyedmojtaba

    2016-04-01

    Aspergillus species can cause ocular morbidity and blindness, and thus, appropriate antifungal therapy is needed. We investigated the in vitro activity of itraconazole, voriconazole, posaconazole, caspofungin, anidulafungin, and amphotericin B against 14 Aspergillus isolates obtained from patients with ocular mycoses, using the CLSI reference broth microdilution methodology. In addition, time-kill assays were performed, exposing each isolate separately to 1-, 4-, and 16-fold concentrations above the minimum inhibitory concentration (MIC) of each antifungal agent. A sigmoid maximum-effect (E max) model was used to fit the time-kill curve data. The drug effect was further evaluated by measuring an increase/decrease in the killing rate of the tested isolates. The MICs of amphotericin B, itraconazole, voriconazole, and posaconazole were 0.5-1.0, 1.0, 0.5-1.0, and 0.25 µg/ml for A. brasiliensis, A. niger, and A. tubingensis isolates, respectively, and 2.0-4.0, 0.5, 1.0 for A. flavus, and 0.12-0.25 µg/ml for A. nomius isolates, respectively. A. calidoustus had the highest MIC range for the azoles (4.0-16.0 µg/ml) among all isolates tested. The minimum effective concentrations of caspofungin and anidulafungin were ≤0.03-0.5 µg/ml and ≤0.03 µg/ml for all isolates, respectively. Posaconazole demonstrated maximal killing rates (E(max) = 0.63 h(-1), r(2) = 0.71) against 14 ocular Aspergillus isolates, followed by amphotericin B (E(max) = 0.39 h(-1), r(2) = 0.87), voriconazole (E(max) = 0.35 h(-1), r(2) = 0.098), and itraconazole (E(max) = 0.01 h(-1), r(2) = 0.98). Overall, the antifungal susceptibility of the non-fumigatus Aspergillus isolates tested was species and antifungal agent dependent. Analysis of the kinetic growth assays, along with consideration of the killing rates, revealed that posaconazole was the most effective antifungal against all of the isolates.

  16. New therapeutic strategies for invasive aspergillosis in the era of azole resistance: how should the prevalence of azole resistance be defined?

    PubMed

    Alanio, Alexandre; Denis, Blandine; Hamane, Samia; Raffoux, Emmanuel; Peffault de la Tour, Régis; Touratier, Sophie; Bergeron, Anne; Bretagne, Stéphane

    2016-08-01

    Given reports showing a high prevalence of azole resistance in Aspergillus fumigatus, alternatives to azole therapy are discussed when a threshold of 10% of azole-resistant environmental isolates is reached. This raises the issue of calculation of this threshold, either on the prevalence of azole-resistant isolates as a whole or on the prevalence of azole-resistant cases in populations at risk of invasive aspergillosis (IA). For isolate evaluation, there are high disparities in routine microbiological procedures for the isolation of A. fumigatus and azole resistance detection. There are also huge differences between the microbiological work-up for diagnosing IA. Some centres rely on galactomannan detection alone without actively trying to culture appropriate samples, which affects reliability of the figures on the prevalence of resistance and thus the threshold of resistance. Moreover, reports from the laboratory could mix up figures from completely different patient populations: frequent azole-resistant isolates from pneumology patients and rare azole-resistant isolates from haematology patients. Therefore, to sum isolates from different specimens and different wards can lead to erroneous calculations for the restricted populations at risk of developing IA. In conclusion, assessing the incidence of azole resistance in A. fumigatus should be based on harmonized consensual microbiological methods and reports should be restricted to IA episodes in identified populations at risk of IA when the issue is to define an operational threshold for modifying recommendations.

  17. Antifungal susceptibility of Malassezia pachydermatis biofilm.

    PubMed

    Figueredo, Luciana A; Cafarchia, Claudia; Otranto, Domenico

    2013-11-01

    Antifungal resistance has been associated with biofilm formation in many microorganisms, but not yet in Malassezia pachydermatis. This saprophytic yeast can cause otitis and dermatitis in dogs and has emerged as an important human pathogen, responsible for systemic infections in neonates in intensive care units. This study aims to evaluate the in vitro antifungal susceptibility of M. pachydermatis strains, in both their planktonic and sessile forms, to fluconazole, miconazole, ketoconazole, itraconazole, posaconazole, terbinafine and voriconazole using the XTT assay and Clinical and Laboratory Standards Institute (CLSI) microdilution method. The minimum inhibitory concentration (MIC) values recorded for each drug were significantly higher for sessile cells relative to planktonic cells to the extent that ≥ 90% of M. pachydermatis strains in their sessile form were classified as resistant to all antifungal agents tested. Data suggest that M. pachydermatis biofilm formation is associated with antifungal resistance, paving the way towards investigating drug resistance mechanisms in Malassezia spp.

  18. Palladium-catalyzed stereocontrolled vinylation of azoles and phenothiazine.

    PubMed

    Lebedev, Artyom Y; Izmer, Vyatcheslav V; Kazyul'kin, Denis N; Beletskaya, Irina P; Voskoboynikov, Alexander Z

    2002-02-21

    [reaction: see text] Vinylation of various azoles (pyrrole, indole, carbazole, and their derivatives) and phenothiazine with vinyl bromides catalyzed by palladium-phosphine complexes results in the respective N-vinylazoles in 30-99% yields. This reaction with cis- and trans-beta-bromostyrenes is stereospecific giving the respective products with full retention of configuration.

  19. Modelling inhibition of avian aromatase by azole pesticides

    PubMed Central

    Saxena, A.K.; Devillers, J.; Bhunia, S.S.; Bro, E.

    2015-01-01

    The potential effects of pesticides and their metabolites on the endocrine system are of major concern to wildlife and human health. In this context, the azole pesticides have earned special attention due to their cytochrome P450 aromatase inhibition potential. Cytochrome P450 aromatase (CYP19) catalyses the conversion of androstenedione and testosterone into oestrone and oestradiol, respectively. Thus, aromatase modulates the oestrogenic balance essential not only for females, but also for male physiology, including gonadal function. Its inhibition affects reproductive organs, fertility and sexual behaviour in humans and wildlife species. Several studies have shown that azole pesticides are able to inhibit human and fish aromatases but the information on birds is lacking. Consequently, it appeared to be of interest to estimate the aromatase inhibition of azoles in three different avian species, namely Gallus gallus, Coturnix coturnix japonica and Taeniopygia guttata. In the absence of the crystal structure of the aromatase enzyme in these bird species, homology models for the individual avian species were constructed using the crystal structure of human aromatase (hAr) (pdb: 3EQM) that showed high sequence similarity for G. gallus (82.0%), T. guttata (81.9%) and C. japonica (81.2%). A homology model with Oncorhynchus mykiss (81.9%) was also designed for comparison purpose. The homology-modelled aromatase for each avian and fish species and crystal structure of human aromatase were selected for docking 46 structurally diverse azoles and related compounds. We showed that the docking behaviour of the chemicals on the different aromatases was broadly the same. We also demonstrated that there was an acceptable level of correlation between the binding score values and the available aromatase inhibition data. This means that the homology models derived on bird and fish species can be used to approximate the potential inhibitory effects of azoles on their aromatase. PMID

  20. Synthesis and antifungal activity of benzo[d]oxazole-4,7-diones.

    PubMed

    Ryu, Chung-Kyu; Lee, Ra-Young; Kim, Na Young; Kim, Yang Hui; Song, Ae Li

    2009-10-15

    Benzo[d]oxazole-4,7-diones were synthesized and tested for in vitro antifungal activity against fungi. Among them tested, many compounds showed good antifungal activity. The results suggest that benzo[d]oxazole-4,7-diones would be potent antifungal agents.

  1. Stereospecific Metabolism of Itraconazole by CYP3A4: Dioxolane Ring Scission of Azole Antifungals

    PubMed Central

    Peng, Chi-Chi; Shi, Wei; Lutz, Justin D.; Kunze, Kent L.; Liu, Jun O.; Nelson, Wendel L.

    2012-01-01

    Itraconazole (ITZ) is a mixture of four cis-stereoisomers that inhibit CYP3A4 potently and coordinate CYP3A4 heme via the triazole nitrogen. However, (2R,4S,2′R)-ITZ and (2R,4S,2′S)-ITZ also undergo stereoselective sequential metabolism by CYP3A4 at a site distant from the triazole ring to 3′-OH-ITZ, keto-ITZ, and N-desalkyl-ITZ. This stereoselective metabolism demonstrates specific interactions of ITZ within the CYP3A4 active site. To further investigate this process, the binding and metabolism of the four trans-ITZ stereoisomers by CYP3A4 were characterized. All four trans-ITZ stereoisomers were tight binding inhibitors of CYP3A4-mediated midazolam hydroxylation (IC50 16–26 nM), and each gave a type II spectrum upon binding to CYP3A4. However, instead of formation of 3′-OH-ITZ, they were oxidized at the dioxolane ring, leading to ring scission and formation of two new metabolites of ITZ. These two metabolites were also formed from the four cis-ITZ stereoisomers, although not as efficiently. The catalytic rates of dioxolane ring scission were similar to the dissociation rates of ITZ stereoisomers from CYP3A4, suggesting that the heme iron is reduced while the triazole moiety coordinates to it and no dissociation of ITZ is necessary before catalysis. The triazole containing metabolite [1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone] also inhibited CYP3A4 (IC50 >15 μM) and showed type II binding with CYP3A4. The dioxolane ring scission appears to be clinically relevant because this metabolite was detected in urine samples from subjects that had been administered the mixture of cis-ITZ isomers. These data suggest that the dioxolane ring scission is a metabolic pathway for drugs that contain this moiety. PMID:22106171

  2. Epidemiology and Antifungal Susceptibility of Bloodstream Fungal Isolates in Pediatric Patients: a Spanish Multicenter Prospective Survey ▿

    PubMed Central

    Pemán, Javier; Cantón, Emilia; Linares-Sicilia, María José; Roselló, Eva María; Borrell, Nuria; Ruiz-Pérez-de-Pipaon, María Teresa; Guinea, Jesús; García, Julio; Porras, Aurelio; García-Tapia, Ana María; Pérez-del-Molino, Luisa; Suárez, Anabel; Alcoba, Julia; García-García, Inmaculada

    2011-01-01

    Data on fungemia epidemiology and antifungal susceptibility of isolates from children are scarce, leading frequently to pediatric empirical treatment based on available adult data. The present study was designed to update the epidemiological, mycological, and in vitro susceptibility data on fungal isolates from children with fungemia in Spain. All fungemia episodes were identified prospectively by blood culture over 13 months at 30 hospitals. Tests of susceptibility to amphotericin B, flucytosine, fluconazole, itraconazole, posaconazole, voriconazole, anidulafungin, caspofungin, and micafungin were performed at participant institutions by a microdilution colorimetric method. New species-specific clinical breakpoints for fluconazole, voriconazole, and echinocandins were also applied. A total of 203 episodes of fungemia in 200 children were identified. A higher proportion of fungal isolates was from general wards than intensive care units (ICU). Candida parapsilosis (46.8%), Candida albicans (36.5%), Candida tropicalis (5.9%), Candida glabrata (3.9%), and Candida guilliermondii (2.5%) were the leading species. C. parapsilosis was the predominant species except in neonates. C. albicans was the most frequent in neonatal ICU settings (51.9%). Intravascular catheter (79.3%), surgery (35%), prematurity (30%), and neutropenia (11%) were the most frequent predisposing factors. Most Candida isolates (95.1%) were susceptible to all antifungals. When the new species-specific clinical breakpoints were applied, all C. parapsilosis isolates were susceptible to echinocandins except one, which was micafungin resistant. This is the largest published series of fungemia episodes in the pediatric setting. C. parapsilosis is the most prevalent species in Spain, followed by C. albicans and C. tropicalis. Resistance to azole and echinocandin agents is extremely rare among Candida species. The fluconazole resistance rate in Spain has decreased in the last 10 years. PMID:22012014

  3. Resistance to antifungal therapies.

    PubMed

    Prasad, Rajendra; Banerjee, Atanu; Shah, Abdul Haseeb

    2017-02-28

    The evolution of antifungal resistance among fungal pathogens has rendered the limited arsenal of antifungal drugs futile. Considering the recent rise in the number of nosocomial fungal infections in immunocompromised patients, the emerging clinical multidrug resistance (MDR) has become a matter of grave concern for medical professionals. Despite advances in therapeutic interventions, it has not yet been possible to devise convincing strategies to combat antifungal resistance. Comprehensive understanding of the molecular mechanisms of antifungal resistance is essential for identification of novel targets that do not promote or delay emergence of drug resistance. The present study discusses features and limitations of the currently available antifungals, mechanisms of antifungal resistance and highlights the emerging therapeutic strategies that could be deployed to combat MDR.

  4. Some O,O',O'',O'''-di/tetra aryldithioimidophonate transition metal complexes derived from catechol and bisphenol-A as antibacterial and antifungal agents.

    PubMed

    Kumar, Vikrant; Ahamad, Tansir; Nishat, N

    2009-02-01

    Two new substituted-thioimidophonate derivatives H1L1 (O,O',O'',O'''-diaryldithioimidophonates) and H1L2 (O,O',O'',O'''-tetra aryldithioimidophonates) were synthesized. These thioimidophonates are potential ligands towards transition metal ions. The reaction of M(II) acetates (M(II)=Mn(II), Co(II), Ni(II), Cu(II), and Zn(II)) with H1L1 and H1L2 resulted in the formation of solid complexes with the composition (L1/L2)(2)M(II). These compounds were characterized through elemental analysis, electrical conductance, infrared, electronic spectra, nmr, magnetic susceptibilities etc. Vibrational mode assignments of nu(PN), nu(PS), nu(MS), phenyl and methyl group bands are made. Structural and bonding changes are correlated with these vibrational frequencies. All the compounds were screened for their antibacterial and antifungal properties and have exhibited potential activities with MIC (0.09-1.50 microg/ml).

  5. The Zinc Finger Protein Mig1 Regulates Mitochondrial Function and Azole Drug Susceptibility in the Pathogenic Fungus Cryptococcus neoformans

    PubMed Central

    Caza, Mélissa; Hu, Guanggan; Price, Michael; Perfect, John R.

    2016-01-01

    ABSTRACT The opportunistic pathogen Cryptococcus neoformans causes fungal meningoencephalitis in immunocompromised individuals. In previous studies, we found that the Hap complex in this pathogen represses genes encoding mitochondrial respiratory functions and tricarboxylic acid (TCA) cycle components under low-iron conditions. The orthologous Hap2/3/4/5 complex in Saccharomyces cerevisiae exerts a regulatory influence on mitochondrial functions, and Hap4 is subject to glucose repression via the carbon catabolite repressor Mig1. In this study, we explored the regulatory link between a candidate ortholog of the Mig1 protein and the HapX component of the Hap complex in C. neoformans. This analysis revealed repression of MIG1 by HapX and activation of HAPX by Mig1 under low-iron conditions and Mig1 regulation of mitochondrial functions, including respiration, tolerance for reactive oxygen species, and expression of genes for iron consumption and iron acquisition functions. Consistently with these regulatory functions, a mig1Δ mutant had impaired growth on inhibitors of mitochondrial respiration and inducers of ROS. Furthermore, deletion of MIG1 provoked a dysregulation in nutrient sensing via the TOR pathway and impacted the pathway for cell wall remodeling. Importantly, loss of Mig1 increased susceptibility to fluconazole, thus further establishing a link between azole antifungal drugs and mitochondrial function. Mig1 and HapX were also required together for survival in macrophages, but Mig1 alone had a minimal impact on virulence in mice. Overall, these studies provide novel insights into a HapX/Mig1 regulatory network and reinforce an association between mitochondrial dysfunction and drug susceptibility that may provide new targets for the development of antifungal drugs. IMPORTANCE Fungal pathogens of humans are difficult to treat, and there is a pressing need to identify new targets for antifungal drugs and to obtain a detailed understanding of fungal

  6. Comparison of echinocandin antifungals

    PubMed Central

    Eschenauer, Gregory; DePestel, Daryl D; Carver, Peggy L

    2007-01-01

    The incidence of invasive fungal infections, especially those due to Aspergillus spp. and Candida spp., continues to increase. Despite advances in medical practice, the associated mortality from these infections continues to be substantial. The echinocandin antifungals provide clinicians with another treatment option for serious fungal infections. These agents possess a completely novel mechanism of action, are relatively well-tolerated, and have a low potential for serious drug–drug interactions. At the present time, the echinocandins are an option for the treatment of infections due Candida spp (such as esophageal candidiasis, invasive candidiasis, and candidemia). In addition, caspofungin is a viable option for the treatment of refractory aspergillosis. Although micafungin is not Food and Drug Administration-approved for this indication, recent data suggests that it may also be effective. Finally, caspofungin- or micafungin-containing combination therapy should be a consideration for the treatment of severe infections due to Aspergillus spp. Although the echinocandins share many common properties, data regarding their differences are emerging at a rapid pace. Anidulafungin exhibits a unique pharmacokinetic profile, and limited cases have shown a potential far activity in isolates with increased minimum inhibitory concentrations to caspofungin and micafungin. Caspofungin appears to have a slightly higher incidence of side effects and potential for drug–drug interactions. This, combined with some evidence of decreasing susceptibility among some strains of Candida, may lessen its future utility. However, one must take these findings in the context of substantially more data and use with caspofungin compared with the other agents. Micafungin appears to be very similar to caspofungin, with very few obvious differences between the two agents. PMID:18360617

  7. INK128 Exhibits Synergy with Azoles against Exophiala spp. and Fusarium spp.

    PubMed Central

    Gao, Lujuan; Sun, Yi; He, Chengyan; Li, Ming; Zeng, Tongxiang; Lu, Qiaoyun

    2016-01-01

    Infections of Exophiala spp. and Fusarium spp. are often chronic and recalcitrant. Systemic disseminations, which mostly occur in immunocompromised patients, are often refractory to available antifungal therapies. The conserved target of rapamycin (TOR) orchestrates cell growth and proliferation in response to nutrients and growth factors, which are important for pathogenicity and virulence. INK128 is a second-generation ATP-competitive TOR inhibitor, which binds the TOR catalytic domain and selectively inhibits TOR. In the present study, we investigated the in vitro activities of INK128 alone and the interactions of INK128 with conventional antifungal drugs including itraconazole, voriconazole, posaconazole, and amphotericin B against 18 strains of Exophiala spp. and 10 strains of Fusarium spp. via broth microdilution checkerboard technique system adapted from Clinical and Laboratory Standards Institute broth microdilution method M38-A2. INK128 alone was inactive against all isolates tested. However, favorable synergistic effects between INK128 and voriconazole were observed in 61% Exophiala strains and 60% Fusarium strains, despite Fusarium strains exhibited high MIC values (4–8 μg/ml) against voriconazole. In addition, synergistic effects of INK128/itraconazole were shown in 33% Exophiala strains and 30% Fusarium strains, while synergy of INK128/posaconazole were observed in 28% Exophiala strains and 30% Fusarium strains. The effective working ranges of INK128 were 0.125–2 μg/ml and 1–4 μg/ml against Exophiala isolates and Fusarium isolates, respectively. No synergistic effect was observed when INK128 was combined with amphotericin B. No antagonism was observed in all combinations. In conclusion, INK128 could enhance the in vitro antifungal activity of voriconazole, itraconazole and posaconazole against Exophiala spp. and Fusarium spp., suggesting that azoles, especially voriconazole, combined with TOR kinase inhibitor might provide a potential strategy

  8. Defensins: antifungal lessons from eukaryotes

    PubMed Central

    Silva, Patrícia M.; Gonçalves, Sónia; Santos, Nuno C.

    2014-01-01

    Over the last years, antimicrobial peptides (AMPs) have been the focus of intense research toward the finding of a viable alternative to current antifungal drugs. Defensins are one of the major families of AMPs and the most represented among all eukaryotic groups, providing an important first line of host defense against pathogenic microorganisms. Several of these cysteine-stabilized peptides present a relevant effect against fungi. Defensins are the AMPs with the broader distribution across all eukaryotic kingdoms, namely, Fungi, Plantae, and Animalia, and were recently shown to have an ancestor in a bacterial organism. As a part of the host defense, defensins act as an important vehicle of information between innate and adaptive immune system and have a role in immunomodulation. This multidimensionality represents a powerful host shield, hard for microorganisms to overcome using single approach resistance strategies. Pathogenic fungi resistance to conventional antimycotic drugs is becoming a major problem. Defensins, as other AMPs, have shown to be an effective alternative to the current antimycotic therapies, demonstrating potential as novel therapeutic agents or drug leads. In this review, we summarize the current knowledge on some eukaryotic defensins with antifungal action. An overview of the main targets in the fungal cell and the mechanism of action of these AMPs (namely, the selectivity for some fungal membrane components) are presented. Additionally, recent works on antifungal defensins structure, activity, and cytotoxicity are also reviewed. PMID:24688483

  9. Defensins: antifungal lessons from eukaryotes.

    PubMed

    Silva, Patrícia M; Gonçalves, Sónia; Santos, Nuno C

    2014-01-01

    Over the last years, antimicrobial peptides (AMPs) have been the focus of intense research toward the finding of a viable alternative to current antifungal drugs. Defensins are one of the major families of AMPs and the most represented among all eukaryotic groups, providing an important first line of host defense against pathogenic microorganisms. Several of these cysteine-stabilized peptides present a relevant effect against fungi. Defensins are the AMPs with the broader distribution across all eukaryotic kingdoms, namely, Fungi, Plantae, and Animalia, and were recently shown to have an ancestor in a bacterial organism. As a part of the host defense, defensins act as an important vehicle of information between innate and adaptive immune system and have a role in immunomodulation. This multidimensionality represents a powerful host shield, hard for microorganisms to overcome using single approach resistance strategies. Pathogenic fungi resistance to conventional antimycotic drugs is becoming a major problem. Defensins, as other AMPs, have shown to be an effective alternative to the current antimycotic therapies, demonstrating potential as novel therapeutic agents or drug leads. In this review, we summarize the current knowledge on some eukaryotic defensins with antifungal action. An overview of the main targets in the fungal cell and the mechanism of action of these AMPs (namely, the selectivity for some fungal membrane components) are presented. Additionally, recent works on antifungal defensins structure, activity, and cytotoxicity are also reviewed.

  10. Azole preexposure affects the Aspergillus fumigatus population in patients.

    PubMed

    Alanio, Alexandre; Cabaret, Odile; Sitterlé, Emilie; Costa, Jean-Marc; Brisse, Sylvain; Cordonnier, Catherine; Bretagne, Stéphane

    2012-09-01

    The relationship between the azole preexposure of 86 patients and the genotype, azole susceptibility, and cyp51A polymorphisms of 110 corresponding Aspergillus fumigatus isolates was explored. Isolates carrying serial polymorphisms (F46Y and M172V with or without N248T with or without D255E with or without E427K) had higher itraconazole MICs (P = 0.04), although <2 μg/ml using the EUCAST methodology, were associated with two genetic clusters (P < 0.001) and with voriconazole preexposure of patients (P = 0.016). Voriconazole preexposure influences the distribution of A. fumigatus isolates with selection of isolates carrying cyp51A polymorphisms and higher itraconazole MICs.

  11. Synthesis of novel quinoline-based 4,5-dihydro-1H-pyrazoles as potential anticancer, antifungal, antibacterial and antiprotozoal agents.

    PubMed

    Ramírez-Prada, Jonathan; Robledo, Sara M; Vélez, Iván D; Crespo, María Del Pilar; Quiroga, Jairo; Abonia, Rodrigo; Montoya, Alba; Svetaz, Laura; Zacchino, Susana; Insuasty, Braulio

    2017-05-05

    A new series of N-substituted 2-pyrazolines 9a-f, 10a-f, 11a-f, 12a-f and 13a-f were obtained from the cyclocondensation reaction of [(7-chloroquinolin-4-yl)amino]chalcones 8a-f with hydrazine hydrate and its derivatives. Fourteen of the synthesized compounds including the starting chalcones were selected by US National Cancer Institute (NCI) for testing their anticancer activity against 60 different human cancer cell lines, with the most important GI50 values ranging from 0.28 to 11.7 μM (0.13-6.05 μg/mL) and LC50 values ranging from 2.6 to > 100 μM (1.2 to > 51.7 μg/mL), for chalcones 8a,d and pyrazolines 10c,d. All compounds were assessed for antibacterial activity against wild type and multidrug resistant gram negative and gram positive bacteria, with MIC values ranging from 31.25 to 500 μg/mL. Additionally, the novel compounds were tested for antifungal and antiparasitic properties. Although these compounds showed mild activity against Candida albicans, chalcones 8a and 8e showed high activity against Cryptococcus neoformans with MIC50 = 7.8 μg/mL. For anti-Plasmodium falciparum activity the 2-pyrazoline 11b was the most active with EC50 = 5.54 μg/mL. Regarding the activity against Trypanosoma cruzi, compound 10a was highly active with EC50 = 0.70 μg/mL. Chalcone 8a had good activity against Leishmania panamensis amastigotes with EC50 = 0.79 μg/mL.

  12. Topical antifungals for seborrhoeic dermatitis

    PubMed Central

    Okokon, Enembe O; Verbeek, Jos H; Ruotsalainen, Jani H; Ojo, Olumuyiwa A; Bakhoya, Victor Nyange

    2015-01-01

    Background Seborrhoeic dermatitis is a chronic inflammatory skin condition that is distributed worldwide. It commonly affects the scalp, face and flexures of the body. Treatment options include antifungal drugs, steroids, calcineurin inhibitors, keratolytic agents and phototherapy. Objectives To assess the effects of antifungal agents for seborrhoeic dermatitis of the face and scalp in adolescents and adults. A secondary objective is to assess whether the same interventions are effective in the management of seborrhoeic dermatitis in patients with HIV/AIDS. Search methods We searched the following databases up to December 2014: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 11), MEDLINE (from 1946), EMBASE (from 1974) and Latin American Caribbean Health Sciences Literature (LILACS) (from 1982). We also searched trials registries and checked the bibliographies of published studies for further trials. Selection criteria Randomised controlled trials of topical antifungals used for treatment of seborrhoeic dermatitis in adolescents and adults, with primary outcome measures of complete clearance of symptoms and improved quality of life. Data collection and analysis Review author pairs independently assessed eligibility for inclusion, extracted study data and assessed risk of bias of included studies. We performed fixed-effect meta-analysis for studies with low statistical heterogeneity and used a random-effects model when heterogeneity was high. Main results We included 51 studies with 9052 participants. Of these, 45 trials assessed treatment outcomes at five weeks or less after commencement of treatment, and six trials assessed outcomes over a longer time frame. We believe that 24 trials had some form of conflict of interest, such as funding by pharmaceutical companies. Among the included studies were 12 ketoconazole trials (N = 3253), 11 ciclopirox trials (N = 3029), two lithium trials (N = 141

  13. Mechanism of inhibition of estrogen biosynthesis by azole fungicides.

    PubMed

    Egbuta, Chinaza; Lo, Jessica; Ghosh, Debashis

    2014-12-01

    Biosynthesis of estrogens from androgens is catalyzed by cytochrome P450 aromatase. Aromatase inhibition by the triazole compounds letrozole (LTZ) and anastrozole is a prevalent therapy for estrogen-dependent postmenopausal breast cancer. Azoles are widely used as agricultural fungicides and antimycotic drugs that target 14α-demethylase. Some were previously shown to inhibit aromatase, thereby raising the possibility of endocrine disruptive effects. However, mechanistic analysis of their inhibition has never been undertaken. We have evaluated the inhibitory effects of 3 common fungicides, bifonazole, imazalil, and flusilazole, in human aromatase purified from placenta and compared them with LTZ, the most potent inhibitor of aromatase. Bifonazole exhibits strong inhibitory effects with an IC50 of 270nM and Ki (Michaeles-Menten inhibition constant) of 68nM, compared with 10nM and 13nM, respectively, for LTZ. The IC50 and Ki are 1100nM and 278nM for imazilil and 3200nM and 547nM for flusilazole, respectively. Analyses of inhibition kinetics suggest that the modes of inhibition by azole fungicides are mixed or competitive, whereas LTZ inhibition could be noncompetitive or mixed. We interpret the inhibition mechanism in the context of the x-ray structure of aromatase-androstenedione complex. Structural data show that aromatase has 3 binding pockets in relation to the heme. The substrate-binding cavity at the heme-distal site closely compliments the structures of the natural substrate, androstenedione, and steroidal aromatase inhibitors. Because the structures of LTZ and the azole fungicides are entirely dissimilar to the androstenedione backbone, the azoles possibly inhibit by binding to a structurally rearranged active site, the 2 other catalytically important sites, or both, in agreement with the kinetics data.

  14. Sensitivity and Performance of Azole Based Energetic Materials

    NASA Astrophysics Data System (ADS)

    Yu, Zijun; Bernstein, Elliot

    2014-03-01

    Imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, and tetrazole based energetic materials are theoretically investigated by employing density functional theory (DFT). Heats of formation (ΔfH0 s) for the studied compounds (298 K) in the gas phase are determined at the B3P86/6-311G (d, p) theory level through isodesmic reactions. The bond dissociation energies (BDEs) corresponding to NO2, NH2, CH3, and Cl removal from carbon or nitrogen positions of the azole ring are also calculated at the B3P86/6-311G (d, p) theory level. The substituent effect of electron-withdrawing (NO2, Cl) and electron-donating (NH2, CH3) groups on the ΔfH0 s and BDEs is discussed. Both electron-withdrawing groups and electron-donating groups (except the CH3 group) dramatically increase the ΔfH0 s of these energetic materials when the substituent is at an N position on the azole ring. For substitution at a C atom on the azole ring, electron-withdrawing and electron-donating groups have different effects on the ΔfH0 s for different azole compounds. A correlation is developed for this series of energetics between impact sensitivity h50 % and the defined sensitivity index (SI): based on this empirical relationship and its extrapolation, the impact sensitivities of compounds for which experiments are not available are provided. The promising energetic compounds in each group, which have potentially good energetic performance and low sensitivity, are 1-amino-2,4,5-trinitroimidazole, 1-amino-3,4,5-trinitropyrazole, 1,4-dinitro-1,2,3-triazole, 1,3-dinitro-1,2,4-triazole, 1-nitrotetrazole. U.S. Army Research Office (ARO, FA9550-10-1-0454).

  15. Systematic Phenotyping of a Large-Scale Candida glabrata Deletion Collection Reveals Novel Antifungal Tolerance Genes

    PubMed Central

    Hiller, Ekkehard; Istel, Fabian; Tscherner, Michael; Brunke, Sascha; Ames, Lauren; Firon, Arnaud; Green, Brian; Cabral, Vitor; Marcet-Houben, Marina; Jacobsen, Ilse D.; Quintin, Jessica; Seider, Katja; Frohner, Ingrid; Glaser, Walter; Jungwirth, Helmut; Bachellier-Bassi, Sophie; Chauvel, Murielle; Zeidler, Ute; Ferrandon, Dominique; Gabaldón, Toni; Hube, Bernhard; d'Enfert, Christophe; Rupp, Steffen; Cormack, Brendan; Haynes, Ken; Kuchler, Karl

    2014-01-01

    The opportunistic fungal pathogen Candida glabrata is a frequent cause of candidiasis, causing infections ranging from superficial to life-threatening disseminated disease. The inherent tolerance of C. glabrata to azole drugs makes this pathogen a serious clinical threat. To identify novel genes implicated in antifungal drug tolerance, we have constructed a large-scale C. glabrata deletion library consisting of 619 unique, individually bar-coded mutant strains, each lacking one specific gene, all together representing almost 12% of the genome. Functional analysis of this library in a series of phenotypic and fitness assays identified numerous genes required for growth of C. glabrata under normal or specific stress conditions, as well as a number of novel genes involved in tolerance to clinically important antifungal drugs such as azoles and echinocandins. We identified 38 deletion strains displaying strongly increased susceptibility to caspofungin, 28 of which encoding proteins that have not previously been linked to echinocandin tolerance. Our results demonstrate the potential of the C. glabrata mutant collection as a valuable resource in functional genomics studies of this important fungal pathogen of humans, and to facilitate the identification of putative novel antifungal drug target and virulence genes. PMID:24945925

  16. Nosocomial Candidiasis: Antifungal Stewardship and the Importance of Rapid Diagnosis.

    PubMed

    Pfaller, Michael A; Castanheira, Mariana

    2016-01-01

    Candidemia and other forms of candidiasis are associated with considerable excess mortality and costs. Despite the addition of several new antifungal agents with improved spectrum and potency, the frequency of Candida infection and associated mortality have not decreased in the past two decades. The lack of rapid and sensitive diagnostic tests has led to considerable overuse of antifungal agents resulting in increased costs, selection pressure for resistance, unnecessary drug toxicity, and adverse drug interactions. Both the lack of timely diagnostic tests and emergence of antifungal resistance pose considerable problems for antifungal stewardship. Whereas antifungal stewardship with a focus on nosocomial candidiasis should be able to improve the administration of antifungal therapy in terms of drug selection, proper dose and duration, source control and de-escalation therapy, an important parameter, timeliness of antifungal therapy, remains a victim of slow and insensitive diagnostic tests. Fortunately, new proteomic and molecular diagnostic tools are improving the time to species identification and detection. In this review we will describe the potential impact that rapid diagnostic testing and antifungal stewardship can have on the management of nosocomial candidiasis.

  17. Phylogenetic Relationships Matter: Antifungal Susceptibility among Clinically Relevant Yeasts

    PubMed Central

    Schmalreck, A. F.; Becker, K.; Fegeler, W.; Czaika, V.; Ulmer, H.; Lass-Flörl, C.

    2014-01-01

    The objective of this study was 2-fold: to evaluate whether phylogenetically closely related yeasts share common antifungal susceptibility profiles (ASPs) and whether these ASPs can be predicted from phylogeny. To address this question, 9,627 yeast strains were collected and tested for their antifungal susceptibility. Isolates were reidentified by considering recent changes in taxonomy and nomenclature. A phylogenetic (PHYLO) code based on the results of multilocus sequence analyses (large-subunit rRNA, small-subunit rRNA, translation elongation factor 1α, RNA polymerase II subunits 1 and 2) and the classification of the cellular neutral sugar composition of coenzyme Q and 18S ribosomal DNA was created to group related yeasts into PHYLO groups. The ASPs were determined for fluconazole, itraconazole, and voriconazole in each PHYLO group. The majority (95%) of the yeast strains were Ascomycetes. After reclassification, a total of 23 genera and 54 species were identified, resulting in an increase of 64% of genera and a decrease of 5% of species compared with the initial identification. These taxa were assigned to 17 distinct PHYLO groups (Ascomycota, n = 13; Basidiomycota, n = 4). ASPs for azoles were similar among members of the same PHYLO group and different between the various PHYLO groups. Yeast phylogeny may be an additional tool to significantly enhance the assessment of MIC values and to predict antifungal susceptibility, thereby more rapidly initiating appropriate patient management. PMID:24366735

  18. Antifungal effect and action mechanism of antimicrobial peptide polybia-CP.

    PubMed

    Wang, Kairong; Jia, Fengjing; Dang, Wen; Zhao, Yanyan; Zhu, Ranran; Sun, Mengyang; Qiu, Shuai; An, Xiaoping; Ma, Zelin; Zhu, Yuanyuan; Yan, Jiexi; Kong, Ziqing; Yan, Wenjin; Wang, Rui

    2016-01-01

    The incidence of life-threatening invasive fungal infections increased significantly in recent years. However, the antifungal therapeutic options are very limited. Antimicrobial peptides are a class of potential lead chemical for the development of novel antifungal agents. Antimicrobial peptide polybia-CP was purified from the venom of the social wasp Polybia paulista. In this study, we synthesized polybia-CP and determined its antifungal effects against a series of Candidian species. Our results showed that polybia-CP has potent antifungal activity and fungicidal activity against the tested fungal cells with a proposed membrane-active action mode. In addition, polybia-CP could induce the increase of cellular reactive oxygen species production, which would attribute to its antifungal activity. In conclusion, the present study suggests that polybia-CP has potential as an antifungal agent or may offer a new strategy for antifungal therapeutic option.

  19. Molecular epidemiology and in-vitro antifungal susceptibility of Aspergillus terreus species complex isolates in Delhi, India: evidence of genetic diversity by amplified fragment length polymorphism and microsatellite typing.

    PubMed

    Kathuria, Shallu; Sharma, Cheshta; Singh, Pradeep Kumar; Agarwal, Puneet; Agarwal, Kshitij; Hagen, Ferry; Meis, Jacques F; Chowdhary, Anuradha

    2015-01-01

    Aspergillus terreus is emerging as an etiologic agent of invasive aspergillosis in immunocompromised individuals in several medical centers in the world. Infections due to A. terreus are of concern due to its resistance to amphotericin B, in vivo and in vitro, resulting in poor response to antifungal therapy and high mortality. Herein we examined a large collection of molecularly characterized, geographically diverse A. terreus isolates (n = 140) from clinical and environmental sources in India for the occurrence of cryptic A. terreus species. The population structure of the Indian A. terreus isolates and their association with those outside India was determined using microsatellite based typing (STR) technique and Amplified Fragment Length Polymorphism analysis (AFLP). Additionally, in vitro antifungal susceptibility of A. terreus isolates was determined against 7 antifungals. Sequence analyses of the calmodulin locus identified the recently described cryptic species A. hortai, comprising 1.4% of Aspergillus section Terrei isolates cultured from cases of aspergilloma and probable invasive aspergillosis not reported previously. All the nine markers used for STR typing of A. terreus species complex proved to be highly polymorphic. The presence of high genetic diversity revealing 75 distinct genotypes among 101 Indian A. terreus isolates was similar to the marked heterogeneity noticed in the 47 global A. terreus population exhibiting 38 unique genotypes mainly among isolates from North America and Europe. Also, AFLP analysis showed distinct banding patterns for genotypically diverse A. terreus isolates. Furthermore, no correlation between a particular genotype and amphotericin B susceptibility was observed. Overall, 8% of the A. terreus isolates exhibited low MICs of amphotericin B. All the echinocandins and azoles (voriconazole, posaconazole and isavuconazole) demonstrated high potency against all the isolates. The study emphasizes the need of molecular

  20. Molecular Epidemiology and In-Vitro Antifungal Susceptibility of Aspergillus terreus Species Complex Isolates in Delhi, India: Evidence of Genetic Diversity by Amplified Fragment Length Polymorphism and Microsatellite Typing

    PubMed Central

    Kathuria, Shallu; Sharma, Cheshta; Singh, Pradeep Kumar; Agarwal, Puneet; Agarwal, Kshitij; Hagen, Ferry; Meis, Jacques F.; Chowdhary, Anuradha

    2015-01-01

    Aspergillus terreus is emerging as an etiologic agent of invasive aspergillosis in immunocompromised individuals in several medical centers in the world. Infections due to A. terreus are of concern due to its resistance to amphotericin B, in vivo and in vitro, resulting in poor response to antifungal therapy and high mortality. Herein we examined a large collection of molecularly characterized, geographically diverse A. terreus isolates (n = 140) from clinical and environmental sources in India for the occurrence of cryptic A. terreus species. The population structure of the Indian A. terreus isolates and their association with those outside India was determined using microsatellite based typing (STR) technique and Amplified Fragment Length Polymorphism analysis (AFLP). Additionally, in vitro antifungal susceptibility of A. terreus isolates was determined against 7 antifungals. Sequence analyses of the calmodulin locus identified the recently described cryptic species A. hortai, comprising 1.4% of Aspergillus section Terrei isolates cultured from cases of aspergilloma and probable invasive aspergillosis not reported previously. All the nine markers used for STR typing of A. terreus species complex proved to be highly polymorphic. The presence of high genetic diversity revealing 75 distinct genotypes among 101 Indian A. terreus isolates was similar to the marked heterogeneity noticed in the 47 global A. terreus population exhibiting 38 unique genotypes mainly among isolates from North America and Europe. Also, AFLP analysis showed distinct banding patterns for genotypically diverse A. terreus isolates. Furthermore, no correlation between a particular genotype and amphotericin B susceptibility was observed. Overall, 8% of the A. terreus isolates exhibited low MICs of amphotericin B. All the echinocandins and azoles (voriconazole, posaconazole and isavuconazole) demonstrated high potency against all the isolates. The study emphasizes the need of molecular

  1. Stepwise emergence of azole, echinocandin and amphotericin B multidrug resistance in vivo in Candida albicans orchestrated by multiple genetic alterations

    PubMed Central

    Jensen, Rasmus Hare; Astvad, Karen Marie Thyssen; Silva, Luis Vale; Sanglard, Dominique; Jørgensen, Rene; Nielsen, Kristian Fog; Mathiasen, Estella Glintborg; Doroudian, Ghazalel; Perlin, David Scott; Arendrup, Maiken Cavling

    2015-01-01

    Objectives The objective of this study was to characterize the underlying molecular mechanisms in consecutive clinical Candida albicans isolates from a single patient displaying stepwise-acquired multidrug resistance. Methods Nine clinical isolates (P-1 to P-9) were susceptibility tested by EUCAST EDef 7.2 and Etest. P-4, P-5, P-7, P-8 and P-9 were available for further studies. Relatedness was evaluated by MLST. Additional genes were analysed by sequencing (including FKS1, ERG11, ERG2 and TAC1) and gene expression by quantitative PCR (CDR1, CDR2 and ERG11). UV-spectrophotometry and GC-MS were used for sterol analyses. In vivo virulence was determined in the insect model Galleria mellonella and evaluated by log-rank Mantel–Cox tests. Results P-1 + P-2 were susceptible, P-3 + P-4 fluconazole resistant, P-5 pan-azole resistant, P-6 + P-7 pan-azole and echinocandin resistant and P-8 + P-9 MDR. MLST supported genetic relatedness among clinical isolates. P-4 harboured four changes in Erg11 (E266D, G307S, G450E and V488I), increased expression of ERG11 and CDR2 and a change in Tac1 (R688Q). P-5, P-7, P-8 and P-9 had an additional change in Erg11 (A61E), increased expression of CDR1, CDR2 and ERG11 (except for P-7) and a different amino acid change in Tac1 (R673L). Echinocandin-resistant isolates harboured the Fks1 S645P alteration. Polyene-resistant P-8 + P-9 lacked ergosterol and harboured a frameshift mutation in ERG2 (F105SfsX23). Virulence was attenuated (but equivalent) in the clinical isolates, but higher than in the azole- and echinocandin-resistant unrelated control strain. Conclusions C. albicans demonstrates a diverse capacity to adapt to antifungal exposure. Potentially novel resistance-inducing mutations in TAC1, ERG11 and ERG2 require independent validation. PMID:26017038

  2. Emerging Threats in Antifungal-Resistant Fungal Pathogens

    PubMed Central

    Sanglard, Dominique

    2016-01-01

    The use of antifungal drugs in the therapy of fungal diseases can lead to the development of antifungal resistance. Resistance has been described for virtually all antifungal agents in diverse pathogens, including Candida and Aspergillus species. The majority of resistance mechanisms have also been elucidated at the molecular level in these pathogens. Drug resistance genes and genome mutations have been identified. Therapeutic choices are limited for the control of fungal diseases, and it is tempting to combine several drugs to achieve better therapeutic efficacy. In the recent years, several novel resistance patterns have been observed, including antifungal resistance originating from environmental sources in Aspergillus fumigatus and the emergence of simultaneous resistance to different antifungal classes (multidrug resistance) in different Candida species. This review will summarize these current trends. PMID:27014694

  3. [S-Acyl derivatives of thiosalicylamides having antifungal activity. II].

    PubMed

    Mazza, M; Modena, T; Montanari, L; Pavanetto, F

    1978-07-01

    Some S-acyl derivatives of N-alkylthiosalicylamides [Table I: substances (I leads to XXXI)] were prepared and tested for antifungal activity. The substances, most of which had not been previously reported, were prepared by condensation of 2-mercapto-N-alkylbenzamides with suitable acylating agents. The antifungal activity of the compounds was tested in vitro against Candida albicans and Trichophyton mentagrophytes. For some compounds the was tested activity against the above strains fungicidal, Candida tropicalis and Saccharomyces cerevisiae. Many of the compounds proved to have high antifungal activity comparable with that of Clotrimazol. The results extended knowledge on the structure-antifungal activity relationships of this class of compounds. The compounds with the highest antifungal activity were: 2-acetylmercapto-N,n-heptylbenzamide (XXVIII); 2-acetylmercapto-5-Cl-N,n-propylbenzamide (XIV); 2-acetylmercapto-N,n-octylbenzamide (XXXI); 2-acetylmercapto-N,n-pentylbenzamide (XXV); 2-acetylmercapto-N,n-hexylbenzamide (XXVII).

  4. Advances in synthetic approach to and antifungal activity of triazoles

    PubMed Central

    Kumar, Nitin; Drabu, Sushma; Sharma, Pramod Kumar

    2011-01-01

    Summary Several five membered ring systems, e.g., triazole, oxadiazole dithiazole and thiadiazole with three heteroatoms at symmetrical or asymmetrical positions have been studied because of their interesting pharmacological properties. In this article our emphasis is on synthetic development and pharmacological activity of the triazole moiety which exhibit a broad spectrum of pharmacological activity such as antifungal, antibacterial, anti-inflammatory and anticancer etc. Triazoles have increased our ability to treat many fungal infections, for example, candidiasis, cryptococcal meningitis, aspergillosis etc. However, mortality due to these infections even with antifungal therapy is still unacceptably high. Therefore, the development of new antifungal agents targeting specific fungal structures or functions is being actively pursued. Rapid developments in molecular mycology have led to a concentrated search for more target antifungals. Although we are entering a new era of antifungal therapy in which we will continue to be challenged by systemic fungal diseases, the options for treatment will have greatly expanded. PMID:21804864

  5. Chemogenomic profiling predicts antifungal synergies

    PubMed Central

    Jansen, Gregor; Lee, Anna Y; Epp, Elias; Fredette, Amélie; Surprenant, Jamie; Harcus, Doreen; Scott, Michelle; Tan, Elaine; Nishimura, Tamiko; Whiteway, Malcolm; Hallett, Michael; Thomas, David Y

    2009-01-01

    Chemotherapies, HIV infections, and treatments to block organ transplant rejection are creating a population of immunocompromised individuals at serious risk of systemic fungal infections. Since single-agent therapies are susceptible to failure due to either inherent or acquired resistance, alternative therapeutic approaches such as multi-agent therapies are needed. We have developed a bioinformatics-driven approach that efficiently predicts compound synergy for such combinatorial therapies. The approach uses chemogenomic profiles in order to identify compound profiles that have a statistically significant degree of similarity to a fluconazole profile. The compounds identified were then experimentally verified to be synergistic with fluconazole and with each other, in both Saccharomyces cerevisiae and the fungal pathogen Candida albicans. Our method is therefore capable of accurately predicting compound synergy to aid the development of combinatorial antifungal therapies. PMID:20029371

  6. Effects of the azole fungicide imazalil on the fathead minnow (Pimephales promelas) steroidogenesis pathway

    EPA Science Inventory

    Azole fungicides, used for both agriculture and human therapeutic applications may disrupt endocrine function of aquatic life. Azole fungicides are designed to inhibit the fungal enzyme lanosterol 14 á-demethylase (cytochrome P450 [CYP] 51). However, they can also interact...

  7. Are azole fungicides losing ground against Septoria wheat disease? Resistance mechanisms in Mycosphaerella graminicola.

    PubMed

    Cools, Hans J; Fraaije, Bart A

    2008-07-01

    There has been a recent rapid decline in the efficacy of some, but not all, azole fungicides in controlling the Septoria leaf blotch pathogen of wheat, Mycosphaerella graminicola. Hans J. Cools and Bart A. Fraaije ask the question: can widespread resistance to all azoles develop in this pathogen?

  8. An azole, an amide and a limonoid from Vepris uguenensis (Rutaceae).

    PubMed

    Cheplogoi, Peter K; Mulholland, Dulcie A; Coombes, Philip H; Randrianarivelojosia, Milijaona

    2008-04-01

    The limonoid derivative, methyl uguenenoate, the azole, uguenenazole, and the amide, uguenenonamide, together with the known furoquinoline alkaloids flindersiamine and maculosidine, and syringaldehyde have been isolated from the root of the East African Rutaceae Vepris uguenensis. While methyl uguenenoate and the furoquinoline alkaloids displayed mild antimalarial activity, the azole and amide were completely inactive.

  9. Uptake of azoles by lamb's lettuce (Valerianella locusta L.) grown in hydroponic conditions.

    PubMed

    García-Valcárcel, Ana I; Loureiro, Iñigo; Escorial, Concepción; Molero, Encarnación; Tadeo, José L

    2016-02-01

    An uptake and translocation study of azole compounds was performed in lamb's lettuce (Valerianella locusta L.) grown in nutrient solution fortified with different azoles. Three azoles, (clotrimazole, fluconazole and propiconazole), which have different physico-chemical properties and are ubiquitous in the aquatic environment, were the compounds selected. An analytical method, based on matrix solid phase dispersion (MSPD) followed by LC-MS/MS determination, was developed to quantify these compounds in aqueous solution and in roots and leaves. The physicochemical properties of azoles are the main factors governing the uptake and plant accumulation. These azoles were detected in leaves indicating their transport within lamb's lettuce. Translocation from nutrient solution to the aerial part of lamb's lettuce was found to be highly dependent on the hydrophobicity of the azole. Clotrimazole accumulates in roots causing necrosis in roots and leaves, whereas fluconazole was the azole with the highest concentration in leaves without causing apparent phytotoxicity symptoms. The assessment of the levels of these azoles in leaves indicates that the risk for human health is negligible.

  10. [Comparative action of 8 azole derivatives against Candida albicans: fungistatic action and cytologic study by scanning electron microscopy].

    PubMed

    Mallie, M; Jouvert, S; Bastide, M; Montes, B; Lebecq, J C; Bastide, J M

    1988-05-01

    The authors compared the in vitro antifungal activity of eight imidazole derivatives (clotrimazole, econazole, isoconazole, ketoconazole, miconazole, oxiconazole, terconazole, tioconazole) against 42 strains of Candida albicans by the agar dilution method using casitone medium. The geometric (G) mean MIC values, the MIC 90 and the MIC 50 values and the corresponding standard deviations of each antifungal agent were determined. The G-MIC values were found to be in the range of 0.008-0.390 micrograms ml-1. The effects of these eight antifungal agents on the ultrastructure of C. albicans yeast cells and spheroplasts were studied by scanning electron microscopy (SEM). The results showed a good correlation between the lesions observed and the structure of the imidazole derivatives tested. On the basis of the SEM results, the compounds could be divided into three groups: (1) ketoconazole and terconazole; (2) econazole, isoconazole, miconazole, oxiconazole and tioconazole; (3) clotrimazole.

  11. Antifungal susceptibility of Candida species isolated from patients with candidemia in southern Taiwan, 2007-2012: impact of new antifungal breakpoints.

    PubMed

    Chen, Yi-Chun; Kuo, Shu-Fang; Chen, Fang-Ju; Lee, Chen-Hsiang

    2017-02-01

    The Clinical and Laboratory Standard Institute (CLSI) revised the clinical breakpoints (CBPs) for the azoles and echinocandins against Candida species in 2012. We aimed to report the epidemiology of candidemia and antifungal susceptibility of Candida species and evaluate the impact of new CBPs on antifungal susceptibility in our region. All blood isolates of Candida species were obtained from 2007 to 2012. The minimum inhibitory concentrations of fluconazole, voriconazole, echinocandins and flucytosine against Candida isolates were determined by Sensititre YeastOne system. Differences in susceptibility rates between the CBPs of previous and revised versions of CLSI were examined. Of 709 Candida isolates, the fluconazole-susceptible rate was 96.5% in Candida albicans, 85.8% in Candida tropicalis and 92.1% in Candida parapsilosis by the revised CBPs. Compared with the susceptibility results by previous CBPs, the marked reductions in susceptibility of C. albicans, C. tropicalis and C. parapsilosis to fluconazole, that of C. tropicalis and C. parapsilosis to voriconazole, that of C. tropicalis and Candida glabrata to anidulafungin and that of C. tropicalis, C. glabrata and Candida krusei to caspofungin by revised CBPs were found. In conclusion, Candida albicans and C. parapsilosis remain highly susceptible to fluconazole. The non-susceptible rates of Candida species to azoles and echinocandins increase with interpretation by the revised CBPs.

  12. Agents.

    PubMed

    Chambers, David W

    2002-01-01

    Although health care is inherently an economic activity, it is inadequately described as a market process. An alternative, grounded in organizational economic theory, is to view professionals and many others as agents, contracted to advance the best interests of their principals (patients). This view untangles some of the ethical conflicts in dentistry. It also helps identify major controllable costs in dentistry and suggests that dentists can act as a group to increase or decrease agency costs, primarily by controlling the bad actors who damage the value of all dentists.

  13. Evaluation of the Effects of Photodynamic Therapy Alone and Combined with Standard Antifungal Therapy on Planktonic Cells and Biofilms of Fusarium spp. and Exophiala spp.

    PubMed

    Gao, Lujuan; Jiang, Shaojie; Sun, Yi; Deng, Meiqi; Wu, Qingzhi; Li, Ming; Zeng, Tongxiang

    2016-01-01

    Infections of Fusarium spp. and Exophiala spp. are often chronic, recalcitrant, resulting in significant morbidity, causing discomfort, disfigurement, social isolation. Systemic disseminations happen in compromised patients, which are often refractory to available antifungal therapies and thereby lead to death. The antimicrobial photodynamic therapy (aPDT) has been demonstrated to effectively inactivate multiple pathogenic fungi and is considered as a promising alternative treatment for mycoses. In the present study, we applied methylene blue (8, 16, and 32 μg/ml) as a photosensitizing agent and light emitting diode (635 ± 10 nm, 12 and 24 J/cm(2)), and evaluated the effects of photodynamic inactivation on five strains of Fusarium spp. and five strains of Exophiala spp., as well as photodynamic effects on in vitro susceptibility to itraconazole, voriconazole, posaconazole and amphotericin B, both planktonic and biofilm forms. Photodynamic therapy was efficient in reducing the growth of all strains tested, exhibiting colony forming unit-reductions of up to 6.4 log10 and 5.6 log10 against planktonic cultures and biofilms, respectively. However, biofilms were less sensitive since the irradiation time was twice longer than that of planktonic cultures. Notably, the photodynamic effects against Fusarium strains with high minimal inhibitory concentration (MIC) values of ≥16, 4-8, 4-8, and 2-4 μg/ml for itraconazole, voriconazole, posaconazole and amphotericin B, respectively, were comparable or even superior to Exophiala spp., despite Exophiala spp. showed relatively better antifungal susceptibility profile. MIC ranges against planktonic cells of both species were up to 64 times lower after aPDT treatment. Biofilms of both species showed high sessile MIC50 (SMIC50) and SMIC80 of ≥16 μg/ml for all azoles tested and variable susceptibilities to amphotericin B, with SMIC ranging between 1 and 16 μg/ml. Biofilms subjected to aPDT exhibited a distinct reduction in

  14. Evaluation of the Effects of Photodynamic Therapy Alone and Combined with Standard Antifungal Therapy on Planktonic Cells and Biofilms of Fusarium spp. and Exophiala spp.

    PubMed Central

    Gao, Lujuan; Jiang, Shaojie; Sun, Yi; Deng, Meiqi; Wu, Qingzhi; Li, Ming; Zeng, Tongxiang

    2016-01-01

    Infections of Fusarium spp. and Exophiala spp. are often chronic, recalcitrant, resulting in significant morbidity, causing discomfort, disfigurement, social isolation. Systemic disseminations happen in compromised patients, which are often refractory to available antifungal therapies and thereby lead to death. The antimicrobial photodynamic therapy (aPDT) has been demonstrated to effectively inactivate multiple pathogenic fungi and is considered as a promising alternative treatment for mycoses. In the present study, we applied methylene blue (8, 16, and 32 μg/ml) as a photosensitizing agent and light emitting diode (635 ± 10 nm, 12 and 24 J/cm2), and evaluated the effects of photodynamic inactivation on five strains of Fusarium spp. and five strains of Exophiala spp., as well as photodynamic effects on in vitro susceptibility to itraconazole, voriconazole, posaconazole and amphotericin B, both planktonic and biofilm forms. Photodynamic therapy was efficient in reducing the growth of all strains tested, exhibiting colony forming unit-reductions of up to 6.4 log10 and 5.6 log10 against planktonic cultures and biofilms, respectively. However, biofilms were less sensitive since the irradiation time was twice longer than that of planktonic cultures. Notably, the photodynamic effects against Fusarium strains with high minimal inhibitory concentration (MIC) values of ≥16, 4-8, 4-8, and 2-4 μg/ml for itraconazole, voriconazole, posaconazole and amphotericin B, respectively, were comparable or even superior to Exophiala spp., despite Exophiala spp. showed relatively better antifungal susceptibility profile. MIC ranges against planktonic cells of both species were up to 64 times lower after aPDT treatment. Biofilms of both species showed high sessile MIC50 (SMIC50) and SMIC80 of ≥16 μg/ml for all azoles tested and variable susceptibilities to amphotericin B, with SMIC ranging between 1 and 16 μg/ml. Biofilms subjected to aPDT exhibited a distinct reduction in SMIC

  15. Copper-catalyzed oxidation of azolines to azoles.

    PubMed

    Dawsey, Anna C; Li, Vincent; Hamilton, Kimberly C; Wang, Jianmei; Williams, Travis J

    2012-07-14

    We report herein convenient, aerobic conditions for the oxidation of thiazolines to thiazoles and data regarding the oxidation mechanism. These reactions feature operationally simple and environmentally benign conditions and proceed in good yield to afford the corresponding azoles, thus enabling the inexpensive preparation of valuable molecular building blocks. Incorporation of a novel diimine-ligated copper catalyst, [((Mes)DAB(Me))Cu(II)(OH(2))(3)](2+) [(-)OTf](2), provides increased reaction efficiency in many cases. In other cases copper-free conditions involving a stoichiometric quantity of base affords superior results.

  16. Point prevalence, microbiology and antifungal susceptibility patterns of oral Candida isolates colonizing or infecting Mexican HIV/AIDS patients and healthy persons.

    PubMed

    Sánchez-Vargas, Luis Octavio; Ortiz-López, Natalia Guadalupe; Villar, María; Moragues, María Dolores; Aguirre, José Manuel; Cashat-Cruz, Miguel; Lopez-Ribot, Jose Luis; Gaitán-Cepeda, Luis Alberto; Quindós, Guillermo

    2005-06-01

    We have conducted a longitudinal study over a 3-year period to address the point prevalence, microbiological characteristics and antifungal susceptibility patterns of yeast isolates colonizing or infecting the oral cavities of 111 HIV-infected (51 adults, 60 children) and 201 non HIV-infected (109 adults, 92 children) Mexican persons. Regarding the epidemiology of oral candidiasis, Candida albicans was the most frequent species isolated. Seventy-one out of 85 isolates from colonized persons were C. albicans (83.5%), 27 isolates of them were from HIV-infected children and 44 from non HIV-infected patients. Sixty-two isolates belonged to serotype A which was the most prevalent serotype of C. albicans. Non-albicans species (Candida glabrata, Candida tropicalis and Candida parapsilosis, and Saccharomyces cerevisiae) were isolated from 16.5% of colonized patients and from 38.5% patients with candidiasis or Candida-related lesions. There were nine episodes of infection or colonization by at least 2 different yeast species. In the case of HIV/AIDS patients, it was determined that yeast carriage was not associated with the number of CD4+ cells or the viral load, but HAART reduced the prevalence of oral candidiasis. Overall, most patients harbored strains in vitro susceptible to fluconazole, however 10.8% of the yeasts were resistant to one or more azole antifungal agents and 29% were intermediate susceptible to them. On the contrary, 5-fluorocytosine was very active against all isolates tested, and amphotericin B was active against 97.9% of them.

  17. Interaction of gelatin with polyenes modulates antifungal activity and biocompatibility of electrospun fiber mats.

    PubMed

    Lakshminarayanan, Rajamani; Sridhar, Radhakrishnan; Loh, Xian Jun; Nandhakumar, Muruganantham; Barathi, Veluchamy Amutha; Kalaipriya, Madhaiyan; Kwan, Jia Lin; Liu, Shou Ping; Beuerman, Roger Wilmer; Ramakrishna, Seeram

    2014-01-01

    Topical application of antifungals does not have predictable or well-controlled release characteristics and requires reapplication to achieve therapeutic local concentration in a reasonable time period. In this article, the efficacy of five different US Food and Drug Administration-approved antifungal-loaded (amphotericin B, natamycin, terbinafine, fluconazole, and itraconazole) electrospun gelatin fiber mats were compared. Morphological studies show that incorporation of polyenes resulted in a two-fold increase in fiber diameter and the mats inhibit the growth of yeasts and filamentous fungal pathogens. Terbinafine-loaded mats were effective against three filamentous fungal species. Among the two azole antifungals compared, the itraconazole-loaded mat was potent against Aspergillus strains. However, activity loss was observed for fluconazole-loaded mats against all of the test organisms. The polyene-loaded mats displayed rapid candidacidal activities as well. Biophysical and rheological measurements indicate strong interactions between polyene antifungals and gelatin matrix. As a result, the polyenes stabilized the triple helical conformation of gelatin and the presence of gelatin decreased the hemolytic activity of polyenes. The polyene-loaded fiber mats were noncytotoxic to primary human corneal and sclera fibroblasts. The reduction of toxicity with complete retention of activity of the polyene antifungal-loaded gelatin fiber mats can provide new opportunities in the management of superficial skin infections.

  18. Interaction of gelatin with polyenes modulates antifungal activity and biocompatibility of electrospun fiber mats

    PubMed Central

    Lakshminarayanan, Rajamani; Sridhar, Radhakrishnan; Loh, Xian Jun; Nandhakumar, Muruganantham; Barathi, Veluchamy Amutha; Kalaipriya, Madhaiyan; Kwan, Jia Lin; Liu, Shou Ping; Beuerman, Roger Wilmer; Ramakrishna, Seeram

    2014-01-01

    Topical application of antifungals does not have predictable or well-controlled release characteristics and requires reapplication to achieve therapeutic local concentration in a reasonable time period. In this article, the efficacy of five different US Food and Drug Administration-approved antifungal-loaded (amphotericin B, natamycin, terbinafine, fluconazole, and itraconazole) electrospun gelatin fiber mats were compared. Morphological studies show that incorporation of polyenes resulted in a two-fold increase in fiber diameter and the mats inhibit the growth of yeasts and filamentous fungal pathogens. Terbinafine-loaded mats were effective against three filamentous fungal species. Among the two azole antifungals compared, the itraconazole-loaded mat was potent against Aspergillus strains. However, activity loss was observed for fluconazole-loaded mats against all of the test organisms. The polyene-loaded mats displayed rapid candidacidal activities as well. Biophysical and rheological measurements indicate strong interactions between polyene antifungals and gelatin matrix. As a result, the polyenes stabilized the triple helical conformation of gelatin and the presence of gelatin decreased the hemolytic activity of polyenes. The polyene-loaded fiber mats were noncytotoxic to primary human corneal and sclera fibroblasts. The reduction of toxicity with complete retention of activity of the polyene antifungal-loaded gelatin fiber mats can provide new opportunities in the management of superficial skin infections. PMID:24920895

  19. Epidemiological and Genomic Landscape of Azole Resistance Mechanisms in Aspergillus Fungi

    PubMed Central

    Hagiwara, Daisuke; Watanabe, Akira; Kamei, Katsuhiko; Goldman, Gustavo H.

    2016-01-01

    Invasive aspergillosis is a life-threatening mycosis caused by the pathogenic fungus Aspergillus. The predominant causal species is Aspergillus fumigatus, and azole drugs are the treatment of choice. Azole drugs approved for clinical use include itraconazole, voriconazole, posaconazole, and the recently added isavuconazole. However, epidemiological research has indicated that the prevalence of azole-resistant A. fumigatus isolates has increased significantly over the last decade. What is worse is that azole-resistant strains are likely to have emerged not only in response to long-term drug treatment but also because of exposure to azole fungicides in the environment. Resistance mechanisms include amino acid substitutions in the target Cyp51A protein, tandem repeat sequence insertions at the cyp51A promoter, and overexpression of the ABC transporter Cdr1B. Environmental azole-resistant strains harboring the association of a tandem repeat sequence and punctual mutation of the Cyp51A gene (TR34/L98H and TR46/Y121F/T289A) have become widely disseminated across the world within a short time period. The epidemiological data also suggests that the number of Aspergillus spp. other than A. fumigatus isolated has risen. Some non-fumigatus species intrinsically show low susceptibility to azole drugs, imposing the need for accurate identification, and drug susceptibility testing in most clinical cases. Currently, our knowledge of azole resistance mechanisms in non-fumigatus Aspergillus species such as A. flavus, A. niger, A. tubingensis, A. terreus, A. fischeri, A. lentulus, A. udagawae, and A. calidoustus is limited. In this review, we present recent advances in our understanding of azole resistance mechanisms particularly in A. fumigatus. We then provide an overview of the genome sequences of non-fumigatus species, focusing on the proteins related to azole resistance mechanisms. PMID:27708619

  20. Soluble material secreted from Penicillium chrysogenum isolate exhibits antifungal activity against Cryphonectria parasitica- the causative agent of the American Chestnut Blight.

    PubMed

    Florjanczyk, Aleksandr; Barnes, Rebecca; Kenney, Adam; Horzempa, Joseph

    2016-04-01

    The American chestnut (Castanea dentata) was once the dominant canopy tree along the eastern region of the United States. Cryphonectria parasitica, the causative agent of chestnut blight, was introduced from Asia in the early 1900's, and obliterated the chestnut population within 50 years. We sought to identify environmental microbes capable of producing factors that were fungicidal or inhibited growth of C. parasitica in the hopes developing a biological control of chestnut blight. We isolated a filamentous fungus that significantly inhibited the growth of C. parasitica upon co-cultivation. Extracellular fractions of this fungal isolate prevented C. parasitica growth, indicating that a potential fungicide was produced by the novel isolate. Sequence analysis of 18S rRNA identified this inhibitory fungus as Penicillium chrysogenum. Furthermore, these extracellular fractions were tested as treatments for blight in vivo using chestnut saplings. Scarred saplings that were treated with the P. chrysogenum extracellular fractions healed subjectively better than those without treatment when inoculated with C. parasitica. These data suggest that material secreted by P. chrysogenum could be used as a treatment for the American chestnut blight. This work may assist the reclamation of the American chestnut in association with breeding programs and blight attenuation. Specifically, treatment of small groves under the right conditions may allow them to remain blight free. Future work will explore the mechanism of action and specific target of the extracellular fraction.

  1. Production and characterization of Iturinic lipopeptides as antifungal agents and biosurfactants produced by a marine pinctada martensii-derived Bacillus mojavensis B0621A.

    PubMed

    Ma, Zongwang; Hu, Jiangchun

    2014-06-01

    Bacillus mojavensis B0621A was isolated from a pearl oyster Pinctada martensii collected from South China Sea. While screening for cyclic lipopeptides potentially useful as lead compounds for biological control against soil-bone fungal plant pathogens, three lipopeptides were isolated and purified from the fermentation broth of B. mojavensis B0621A via vacuum flash chromatography coupled with reversed-phase high performance liquid chromatography (RP-HPLC). The structural characterization and identification of these cyclic lipopeptides were performed by tandem mass spectrometry (MS/MS) combined with gas chromatography-mass spectrometry (GC-MS) analysis as well as chemical degradation. These lipopeptides were finally characterized as homologues of mojavensins, which contained identical amino acids back bones of asparagine1, tyrosine2, asparagine3, glutamine4, proline5, asparagine6, and asparagine7 and differed from each other by their saturated β-amino fatty acid chain residues, namely, iso-C14 mojavensin, iso-C16 mojavensin, and anteiso-C17 mojavensin, respectively. All lipopeptide isomers, especially iso-C16 mojavensin and anteiso-C17 mojavensin, displayed moderate antagonism and dose-dependent activity against several formae speciales of Fusarium oxysporum and presented surface tension activities. These properties demonstrated that the lipopeptides produced by B. mojavensis B0621A may be useful as biological control agent to fungal plant pathogens.

  2. Soluble material secreted from Penicillium chrysogenum isolate exhibits antifungal activity against Cryphonectria parasitica- the causative agent of the American Chestnut Blight

    PubMed Central

    Florjanczyk, Aleksandr; Barnes, Rebecca; Kenney, Adam; Horzempa, Joseph

    2016-01-01

    The American chestnut (Castanea dentata) was once the dominant canopy tree along the eastern region of the United States. Cryphonectria parasitica, the causative agent of chestnut blight, was introduced from Asia in the early 1900's, and obliterated the chestnut population within 50 years. We sought to identify environmental microbes capable of producing factors that were fungicidal or inhibited growth of C. parasitica in the hopes developing a biological control of chestnut blight. We isolated a filamentous fungus that significantly inhibited the growth of C. parasitica upon co-cultivation. Extracellular fractions of this fungal isolate prevented C. parasitica growth, indicating that a potential fungicide was produced by the novel isolate. Sequence analysis of 18S rRNA identified this inhibitory fungus as Penicillium chrysogenum. Furthermore, these extracellular fractions were tested as treatments for blight in vivo using chestnut saplings. Scarred saplings that were treated with the P. chrysogenum extracellular fractions healed subjectively better than those without treatment when inoculated with C. parasitica. These data suggest that material secreted by P. chrysogenum could be used as a treatment for the American chestnut blight. This work may assist the reclamation of the American chestnut in association with breeding programs and blight attenuation. Specifically, treatment of small groves under the right conditions may allow them to remain blight free. Future work will explore the mechanism of action and specific target of the extracellular fraction. PMID:27274909

  3. Antifungal compounds from cyanobacteria.

    PubMed

    Shishido, Tânia K; Humisto, Anu; Jokela, Jouni; Liu, Liwei; Wahlsten, Matti; Tamrakar, Anisha; Fewer, David P; Permi, Perttu; Andreote, Ana P D; Fiore, Marli F; Sivonen, Kaarina

    2015-04-13

    Cyanobacteria are photosynthetic prokaryotes found in a range of environments. They are infamous for the production of toxins, as well as bioactive compounds, which exhibit anticancer, antimicrobial and protease inhibition activities. Cyanobacteria produce a broad range of antifungals belonging to structural classes, such as peptides, polyketides and alkaloids. Here, we tested cyanobacteria from a wide variety of environments for antifungal activity. The potent antifungal macrolide scytophycin was detected in Anabaena sp. HAN21/1, Anabaena cf. cylindrica PH133, Nostoc sp. HAN11/1 and Scytonema sp. HAN3/2. To our knowledge, this is the first description of Anabaena strains that produce scytophycins. We detected antifungal glycolipopeptide hassallidin production in Anabaena spp. BIR JV1 and HAN7/1 and in Nostoc spp. 6sf Calc and CENA 219. These strains were isolated from brackish and freshwater samples collected in Brazil, the Czech Republic and Finland. In addition, three cyanobacterial strains, Fischerella sp. CENA 298, Scytonema hofmanni PCC 7110 and Nostoc sp. N107.3, produced unidentified antifungal compounds that warrant further characterization. Interestingly, all of the strains shown to produce antifungal compounds in this study belong to Nostocales or Stigonematales cyanobacterial orders.

  4. FK520 interacts with the discrete intrahelical amino acids of multidrug transporter Cdr1 protein and acts as antagonist to selectively chemosensitize azole-resistant clinical isolates of Candida albicans.

    PubMed

    Nim, Shweta; Rawal, Manpreet K; Prasad, Rajendra

    2014-06-01

    FK520, a homolog of antifungal FK506, displays fungicidal synergism with azoles in Candida albicans and inhibits drug efflux mediated by ABC multidrug transporter. This study establishes the molecular basis of interaction of FK520 with Cdr1 protein, which is one of the major ABC multidrug transporters of C. albicans. For this, we have exploited an in-house library of Cdr1 protein consisting of 252 mutant variants where the entire primary structure of the two transmembrane domains comprising of 12 transmembrane helices was subjected to alanine scanning. With these mutant variants of Cdr1 protein, we could identify the critical amino acids of the transporter protein, which if replaced with alanine, not only abrogated FK520-dependent competitive inhibition of drug efflux but simultaneously decreased susceptibility to azoles. Notably, the replacement of most of the residues with alanine was inconsequential; however, there were close to 13% mutant variants, which showed abrogation of drug efflux and reversal of fungicidal synergy with azoles. Of note, all the intrahelical residues of Cdr1 protein, which abrogated inhibitor's ability to block the efflux and reversed fungicidal synergy, were common. Taken together, our results provide evidence of cross-talk of FK520 with Cdr1 by interacting with the select intrahelical residues of the protein to chemosensitize isolates of Candida.

  5. Can agricultural fungicides accelerate the discovery of human antifungal drugs?

    PubMed

    Myung, Kyung; Klittich, Carla J R

    2015-01-01

    Twelve drugs from four chemical classes are currently available for treatment of systemic fungal infections in humans. By contrast, more than 100 structurally distinct compounds from over 30 chemical classes have been developed as agricultural fungicides, and these fungicides target many modes of action not represented among human antifungal drugs. In this article we introduce the diverse aspects of agricultural fungicides and compare them with human antifungal drugs. We propose that the information gained from the development of agricultural fungicides can be applied to the discovery of new mechanisms of action and new antifungal agents for the management of human fungal infections.

  6. Antifungal susceptibility and molecular typing of 115 Candida albicans isolates obtained from vulvovaginal candidiasis patients in 3 Shanghai maternity hospitals.

    PubMed

    Ying, Chunmei; Zhang, Hongju; Tang, Zhenhua; Chen, Huifen; Gao, Jing; Yue, Chaoyan

    2016-05-01

    In our multicenter study, we studied the distribution of Candida species in vulvovaginal candidiasis patients and investigated antifungal susceptibility profile and genotype of Candida albicans in vaginal swab. A total of 115 Candida albicans strains were detected in 135 clinical isolates. Minimum inhibitory concentration determinations showed that 83% and 81% of the 115 Candida albicans strains were susceptible to fluconazole and voriconazole. Randomly amplified polymorphic DNA analysis (RAPD) was applied to identify clonally related isolates from different patients at the local level. All tested strains were classified into genotype A (77.4%), genotype B (18.3%), and genotype C (4.3%). Genotype A was further classified into five subtypes and genotype B into two subtypes.Candida albicans was the dominant pathogen of vulvovaginal candidiasis, the majority belonging to genotype A in this study. Exposure to azoles is a risk factor for the emergence of azole resistance among Candida albicans isolated from VVC patients.

  7. In Vitro Antifungal Susceptibilities of Five Species of Sporothrix▿

    PubMed Central

    Marimon, Rita; Serena, Carolina; Gené, Josepa; Cano, Josep; Guarro, Josep

    2008-01-01

    Ninety-two isolates belonging to five species of the Sporothrix schenckii complex were tested in vitro against 12 antifungal agents, using a reference microdilution method. There were significant differences among the species; Sporothrix brasiliensis was the species that showed the best response to antifungals, and S. mexicana had the worst response. In general, terbinafine was the most active drug, followed by ketoconazole and posaconazole. PMID:18039919

  8. Antibacterial and antifungal activity of Indonesian ethnomedical plants.

    PubMed

    Goun, E; Cunningham, G; Chu, D; Nguyen, C; Miles, D

    2003-09-01

    Methylene chloride and methanol extracts of 20 Indonesian plants with ethnomedical uses have been assessed for in vitro antibacterial and antifungal properties by disk diffusion method. Extracts of the six plants: Terminalia catappa, Swietenia mahagoni Jacq., Phyllanthus acuminatus, Ipomoea spp., Tylophora asthmatica and Hyptis brevipes demonstrated high activity in this bioassay system. These findings should stimulate the search for novel, natural product such as new antibacterial and antifungal agents.

  9. Microbiological screening of Irish patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy reveals persistence of Candida albicans strains, gradual reduction in susceptibility to azoles, and incidences of clinical signs of oral candidiasis without culture evidence.

    PubMed

    McManus, Brenda A; McGovern, Eleanor; Moran, Gary P; Healy, Claire M; Nunn, June; Fleming, Pádraig; Costigan, Colm; Sullivan, Derek J; Coleman, David C

    2011-05-01

    Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) are prone to chronic mucocutaneous candidiasis, which is often treated with azoles. The purpose of this study was to characterize the oral Candida populations from 16 Irish APECED patients, who comprise approximately half the total number identified in Ireland, and to examine the effect of intermittent antifungal therapy on the azole susceptibility patterns of Candida isolates. Patients attended between one and four clinical evaluations over a 5-year period, providing oral rinses and/or oral swab samples each time. Candida was recovered from 14/16 patients, and Candida albicans was the only Candida species identified. Interestingly, clinical diagnosis of candidiasis did not correlate with microbiological evidence of Candida infection at 7/22 (32%) clinical assessments. Multilocus sequence typing analysis of C. albicans isolates recovered from the same patients on separate occasions identified the same sequence type each time. Fluconazole resistance was detected in isolates from one patient, and isolates exhibiting a progressive reduction in itraconazole and/or fluconazole susceptibility were identified in a further 3/16 patients, in each case correlating with the upregulation of CDR- and MDR-encoded efflux pumps. Mutations were also identified in the ERG11 and the TAC1 genes of isolates from these four patients; some of these mutations have previously been associated with azole resistance. The findings suggest that alternative Candida treatment options, other than azoles such as chlorhexidine, should be considered in APECED patients and that clinical diagnosis of oral candidiasis should be confirmed by culture prior to the commencement of anti-Candida therapy.

  10. Posttreatment Antifungal Resistance among Colonizing Candida Isolates in Candidemia Patients: Results from a Systematic Multicenter Study

    PubMed Central

    Jensen, R. H.; Johansen, H. K.; Søes, L. M.; Lemming, L. E.; Rosenvinge, F. S.; Nielsen, L.; Olesen, B.; Kristensen, L.; Dzajic, E.; Astvad, K. M. T.

    2015-01-01

    The prevalence of intrinsic and acquired resistance among colonizing Candida isolates from patients after candidemia was investigated systematically in a 1-year nationwide study. Patients were treated at the discretion of the treating physician. Oral swabs were obtained after treatment. Species distributions and MIC data were investigated for blood and posttreatment oral isolates from patients exposed to either azoles or echinocandins for <7 or ≥7 days. Species identification was confirmed using matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) and internal transcribed spacer (ITS) sequencing, susceptibility was examined by EUCAST EDef 7.2 methodology, echinocandin resistance was examined by FKS sequencing, and genetic relatedness was examined by multilocus sequence typing (MLST). One hundred ninety-three episodes provided 205 blood and 220 oral isolates. MLST analysis demonstrated a genetic relationship for 90% of all paired blood and oral isolates. Patients exposed to azoles for ≥7 days (n = 93) had a significantly larger proportion of species intrinsically less susceptible to azoles (particularly Candida glabrata) among oral isolates than among initial blood isolates (36.6% versus 12.9%; P < 0.001). A similar shift toward species less susceptible to echinocandins among 85 patients exposed to echinocandins for ≥7 days was not observed (4.8% of oral isolates versus 3.2% of blood isolates; P > 0.5). Acquired resistance in Candida albicans was rare (<5%). However, acquired resistance to fluconazole (29.4%; P < 0.05) and anidulafungin (21.6%; P < 0.05) was common in C. glabrata isolates from patients exposed to either azoles or echinocandins. Our findings suggest that the colonizing mucosal microbiota may be an unrecognized reservoir of resistant Candida species, especially C. glabrata, following treatment for candidemia. The resistance rates were high, raising concern in general for patients exposed to antifungal

  11. High Virulence and Antifungal Resistance in Clinical Strains of Candida albicans

    PubMed Central

    Monroy-Pérez, Eric; Paniagua-Contreras, Gloria Luz; Rodríguez-Purata, Pamela; Vaca-Paniagua, Felipe; Vázquez-Villaseñor, Marco; Díaz-Velásquez, Clara; Uribe-García, Alina

    2016-01-01

    Antifungal resistance and virulence properties of Candida albicans are a growing health problem worldwide. To study the expression of virulence and azole resistance genes in 39 clinical strains of C. albicans, we used a model of infection of human vaginal epithelial cells with C. albicans strains isolated from Mexican women with vulvovaginal candidiasis (VVC). The strains were identified by PCR amplification of the ITS1 and ITS2 regions of rRNA. The detection and expression of virulence genes and azole resistance genes MDR1 and CDR1 were performed using PCR and RT-PCR, respectively. All strains were sensitive to nystatin and 38 (97.4%) and 37 (94.9%) were resistant to ketoconazole and fluconazole, respectively. ALS1, SAP4–SAP6, LIP1, LIP2, LIP4, LIP6, LIP7, LIP9, LIP10, and PLB1-PLB2 were present in all strains; SAP1 was identified in 37 (94.8%) isolates, HWP1 in 35 (89.7%), ALS3 in 14 (35.8%), and CDR1 in 26 (66.6%). In nearly all of the strains, ALS1, HWP1, SAP4–SAP6, LIP1–LIP10, PLB1, and PLB2 were expressed, whereas CDR1 was expressed in 20 (51.3%) and ALS3 in 14 (35.8%). In our in vitro model of infection with C. albicans, the clinical strains showed different expression profiles of virulence genes in association with the azole resistance gene CDR1. The results indicate that the strains that infect Mexican patients suffering from VVC are highly virulent and virtually all are insensitive to azoles. PMID:28058052

  12. Additive and synergistic antiandrogenic activities of mixtures of azol fungicides and vinclozolin

    SciTech Connect

    Christen, Verena; Crettaz, Pierre; Fent, Karl

    2014-09-15

    Objective: Many pesticides including pyrethroids and azole fungicides are suspected to have an endocrine disrupting property. At present, the joint activity of compound mixtures is only marginally known. Here we tested the hypothesis that the antiandrogenic activity of mixtures of azole fungicides can be predicted by the concentration addition (CA) model. Methods: The antiandrogenic activity was assessed in MDA-kb2 cells. Following assessing single compounds activities mixtures of azole fungicides and vinclozolin were investigated. Interactions were analyzed by direct comparison between experimental and estimated dose–response curves assuming CA, followed by an analysis by the isobole method and the toxic unit approach. Results: The antiandrogenic activity of pyrethroids deltamethrin, cypermethrin, fenvalerate and permethrin was weak, while the azole fungicides tebuconazole, propiconazole, epoxiconazole, econazole and vinclozolin exhibited strong antiandrogenic activity. Ten binary and one ternary mixture combinations of five antiandrogenic fungicides were assessed at equi-effective concentrations of EC{sub 25} and EC{sub 50}. Isoboles indicated that about 50% of the binary mixtures were additive and 50% synergistic. Synergism was even more frequently indicated by the toxic unit approach. Conclusion: Our data lead to the conclusion that interactions in mixtures follow the CA model. However, a surprisingly high percentage of synergistic interactions occurred. Therefore, the mixture activity of antiandrogenic azole fungicides is at least additive. Practice: Mixtures should also be considered for additive antiandrogenic activity in hazard and risk assessment. Implications: Our evaluation provides an appropriate “proof of concept”, but whether it equally translates to in vivo effects should further be investigated. - Highlights: • Humans are exposed to pesticide mixtures such as pyrethroids and azole fungicides. • We assessed the antiandrogenicity of

  13. Antifungal Activity of Brazilian Propolis Microparticles against Yeasts Isolated from Vulvovaginal Candidiasis

    PubMed Central

    Dota, Kelen Fátima Dalben; Consolaro, Marcia Edilaine Lopes; Svidzinski, Terezinha Inez Estivalet; Bruschi, Marcos Luciano

    2011-01-01

    Propolis, a resinous compound produced by Apis mellifera L. bees, is known to possess a variety of biological activities and is applied in the therapy of various infectious diseases. The aim of this study was to evaluate the in vitro antifungal activity of propolis ethanol extract (PE) and propolis microparticles (PMs) obtained from a sample of Brazilian propolis against clinical yeast isolates of importance in the vulvovaginal candidiasis (VVC). PE was used to prepare the microparticles. Yeast isolates (n = 89), obtained from vaginal exudates of patients with VVC, were exposed to the PE and the PMs. Moreover, the main antifungal drugs used in the treatment of VVC (Fluconazole, Voriconazole, Itraconazole, Ketoconazole, Miconazole and Amphotericin B) were also tested. Minimum inhibitory concentration (MIC) was determined according to the standard broth microdilution method. Some Candida albicans isolates showed resistance or dose-dependent susceptibility for the azolic drugs and Amphotericin B. Non-C. albicans isolates showed more resistance and dose-dependent susceptibility for the azolic drugs than C. albicans. However, all of them were sensitive or dose-dependent susceptible for Amphotericin B. All yeasts were inhibited by PE and PMs, with small variation, independent of the species of yeast. The overall results provided important information for the potential application of PMs in the therapy of VVC and the possible prevention of the occurrence of new symptomatic episodes. PMID:21607012

  14. The structure of alkali metal derivatives of azoles: N-sigma versus pi structures.

    PubMed

    Blanco, Fernando; Alkorta, Ibon; Elguero, Jose

    2008-08-21

    High level ab initio calculations have been used to study the relative stability of N-sigma and pi configurations of the neutral alkaline derivatives of azoles. The N-sigma structure is the one normally expected for nonionized azolate salts. However, the results show that in the case of the pyrrole and imidazole the pi configuration is more stable than the N-sigma one. The preference of the N-sigma vs pi configurations is related to the presence or the absence of two contiguous nitrogen atoms in the azole ring. A search in the CSD shows that some pyrrolate and imidazolate salts exist in solid phase in the pi configuration.

  15. In vitro antifungal activity of topical and systemic antifungal drugs against Malassezia species.

    PubMed

    Carrillo-Muñoz, Alfonso Javier; Rojas, Florencia; Tur-Tur, Cristina; de Los Ángeles Sosa, María; Diez, Gustavo Ortiz; Espada, Carmen Martín; Payá, María Jesús; Giusiano, Gustavo

    2013-09-01

    The strict nutritional requirements of Malassezia species make it difficult to test the antifungal susceptibility. Treatments of the chronic and recurrent infections associated with Malassezia spp. are usually ineffective. The objective of this study was to obtain in vitro susceptibility profile of 76 clinical isolates of Malassezia species against 16 antifungal drugs used for topical or systemic treatment. Isolates were identified by restriction fragment length polymorphism. Minimal inhibitory concentrations (MIC) were obtained by a modified microdilution method based on the Clinical Laboratory Standards Institute reference document M27-A3. The modifications allowed a good growth of all tested species. High in vitro antifungal activity of most tested drugs was observed, especially triazole derivatives, except for fluconazole which presented the highest MICs and widest range of concentrations. Ketoconazole and itraconazole demonstrated a great activity. Higher MICs values were obtained with Malassezia furfur indicating a low susceptibility to most of the antifungal agents tested. Malassezia sympodialis and Malassezia pachydermatis were found to be more-susceptible species than M. furfur, Malassezia globosa, Malassezia slooffiae and Malassezia restricta. Topical substances were also active but provide higher MICs than the compounds for systemic use. The differences observed in the antifungals activity and interspecies variability demonstrated the importance to studying the susceptibility profile of each species to obtain reliable information for defining an effective treatment regimen.

  16. Evaluation of antifungal combination against Cryptococcus spp.

    PubMed

    Reichert-Lima, Franqueline; Busso-Lopes, Ariane F; Lyra, Luzia; Peron, Isabela Haddad; Taguchi, Hideaki; Mikami, Yuzuru; Kamei, Katsuiko; Moretti, Maria Luiza; Schreiber, Angelica Z

    2016-09-01

    The second cause of death among systemic mycoses, cryptococcosis treatment represents a challenge since that 5-flucytosine is not currently available in Brazil. Looking for alternatives, this study evaluated antifungal agents, alone and combined, correlating susceptibility to genotypes. Eighty Cryptococcus clinical isolates were genotyped by URA5 gene restriction fragment length polymorphism. Antifungal susceptibility was assessed following CLSI-M27A3 for amphotericin (AMB), 5-flucytosine (5FC), fluconazole (FCZ), voriconazole (VRZ), itraconazole (ITZ) and terbinafine (TRB). Drug interaction chequerboard assay evaluated: AMB + 5FC, AMB + FCZ, AMB + TRB and FCZ + TRB. Molecular typing divided isolates into 14 C. deuterogattii (VGII) and C. neoformans isolates were found to belong to genotype VNI (n = 62) and VNII (n = 4). C. neoformans VNII was significantly less susceptible than VNI (P = 0.0407) to AMB; C. deuterogattii was significantly less susceptible than VNI and VNII to VRZ (P < 0.0001). C. deuterogattii was less susceptible than C. neoformans VNI for FCZ (P = 0.0170), ITZ (P < 0.0001) and TRB (P = 0.0090). The combination FCZ + TRB showed 95.16% of synergistic effect against C. neoformans genotype VNI isolates and all combinations showed 100% of synergism against genotype VNII isolates, suggesting the relevance of cryptococcal genotyping as it is widely known that the various genotypes (now species) have significant impact in antifungal susceptibilities and clinical outcome. In difficult-to-treat cryptococcosis, terbinafine and different antifungal combinations might be alternatives to 5FC.

  17. Posaconazole prophylaxis in experimental azole-resistant invasive pulmonary aspergillosis.

    PubMed

    Seyedmousavi, Seyedmojtaba; Mouton, Johan W; Melchers, Willem J G; Verweij, Paul E

    2015-03-01

    We investigated the efficacy of posaconazole prophylaxis in preventing invasive aspergillosis due to azole-resistant Aspergillus fumigatus isolates. Using a neutropenic murine model of pulmonary infection, posaconazole prophylaxis was evaluated using three isogenic clinical isolates, with posaconazole MICs of 0.063 mg/liter (wild type), 0.5 mg/liter (F219I mutation), and 16 mg/liter. A fourth isolate harboring TR34/L98H (MIC of 0.5 mg/liter) was also tested. Posaconazole prophylaxis was effective in A. fumigatus with posaconazole MICs of ≤0.5 mg/liter, where 100% survival was reached. However, breakthrough infection was observed in mice infected with the isolate for which the posaconazole MIC was >16 mg/liter.

  18. Antifungal susceptibilities of Candida species isolated from the patients with vaginal candidiasis.

    PubMed

    Nagashima, Masahito; Yamagishi, Yuka; Mikamo, Hiroshige

    2016-02-01

    There have been the current Japanese data on susceptibility testing for Candida isolates from vaginal candidiasis. The in vitro activities of therapeutic antifungal drugs for vulvovaginal candidiasis (VVC); miconazole (MCZ), itraconazole (ITCZ), fluconazole (FLCZ), clotrimazole (CTZ), oxiconazole (OCZ), isoconazole (ICZ) and bifonazole (BFZ) against vaginal isolates. Fifty-four strains Candida albicans and 19 strains of Candida glabrata were evaluated using a broth microdilution method specified by Clinical Laboratories Standard Institute (CLSI) document M27-A3. The MIC90 of each drug, MCZ, ITCZ, FLCZ, CTZ, OCZ, ICZ and BFZ, against C. albicans and C. glabrata isolates were 0.25, 0.12, 1, 0.06, 0.12, 0.12 and 1 μg/ml and 1, 1, 8, 0.5, 0.25, 0.5 and 1 μg/ml respectively. The activities of these drugs, except for BFZ, against C. glabrata were lower than that of C. albicans. There was one azole-resistant isolate in C. glabrata of which MIC of FLCZ is > 64 μg/ml and this isolate had cross resistance to other antifungal drugs tested. These results suggest that antifungal drugs for treatment of VVC continues to have potent antifungal activities against C. albicans and C. glabrata isolates from vaginitis. CTZ, OCZ and ICZ susceptibility of FLCZ low susceptibility C. glabrata are relatively higher than MCZ, ITCZ and FLCZ.

  19. Antifungal activity of itraconazole and voriconazole against clinical isolates obtained from animals with mycoses.

    PubMed

    Okabayashi, Ken; Imaji, Mashio; Osumi, Takafumi; Murakami, Yoshihiko; Maruyama, Haruhiko; Kano, Rui; Hasegawa, Atsuhiko; Watanabe, Toshi

    2009-01-01

    Animal mycosis, particularly deep mycosis, is one of the most challenging conditions encountered by veterinarians. Pathogens causing mycotic infections in animals include fungi such as Cryptococcus neoformans, Candida spp., and Aspergillus spp. The antifungal drugs used for the treatment of deep mycoses in animals as well as humans are polyenes and azoles. However, the sensitivity of clinical isolates obtained from animals toward these drugs has rarely been assayed. In this study, the antifungal activities of itraconazole and voriconazole against clinical isolates of C. neoformans, Candida spp., and A. fumigatus isolated from animals with mycoses were examined using the broth microdilution method performed according to the guidelines provided by the Clinical and Laboratory Standards Institute. The minimum inhibitory concentrations (MICs) of itraconazole toward the C. neoformans, Candida spp., and A. fumigatus isolates were 0.125 - 1, 0.125 - 2, and 0.25 - 2 microg/ml, respectively, and those of voriconazole were 0.0625 - 0.5, < or =0.0313 - 0.0625, and 0.0625 - 1 microg/ml, respectively. The results of the MIC analyses implied that the fungal isolates obtained from infected animals exhibit an equivalent degree of susceptibility to itraconazole and voriconazole, as is observed in the case of isolates obtained from humans. The appropriate antifungal therapeutic strategy for the treatment of mycoses in animals must be selected taking into consideration the host immune status and organ function as well as the in vitro sensitivity of the pathogens to antifungal drugs.

  20. Novel Thiazolidinone-Azole Hybrids: Design, Synthesis and Antimycobacterial Activity Studies

    PubMed Central

    Eroglu, Barbaros; Ozadali-Sari, Keriman; Unsal-Tan, Oya; Dharmarajan, Sriram; Yogeeswari, Perumal; Balkan, Ayla

    2016-01-01

    To develop novel antimycobacterial agents, a new series of thiazolidinone-azole hybrids 4a-b, 5a-b and 6-13 were designed and synthesized. Thiazolidin-4-ones (4a-b and 5a-b) were obtained by the reaction of Schiff bases and hydrazones (2a-b and 3a-b) with mercaptoacetic acid. 5-Benzylidene derivatives (6-13) were gained by treatment of 5a-b with appropriate benzaldehydes according to Knoevenagel condensation. To evaluate their structures 1H NMR, IR, mass spectrometry and elemental analysis data were used. The target compounds were screened for their antimycobacterial activity against M. tuberculosis H37Rv strain using the microplate alamar blue assay method. Among them, 6, 10 and 12 (MIC: 14.27-14.74 μM) were found as most active compounds in the series. It was seen that both phenylamino and benzylidene substitutions on thiazolidin-4-one ring caused an improvement in the antimycobacterial activity. PMID:28243274

  1. Antifungal susceptibilities of bloodstream isolates of Candida species from nine hospitals in Korea: application of new antifungal breakpoints and relationship to antifungal usage.

    PubMed

    Won, Eun Jeong; Shin, Jong Hee; Choi, Min Ji; Lee, Wee Gyo; Park, Yeon-Joon; Uh, Young; Kim, Shine-Young; Lee, Mi-Kyung; Kim, Soo Hyun; Shin, Myung Geun; Suh, Soon Pal; Ryang, Dong Wook

    2015-01-01

    We applied the new clinical breakpoints (CBPs) of the Clinical and Laboratory Standards Institute (CLSI) to a multicenter study to determine the antifungal susceptibility of bloodstream infection (BSI) isolates of Candida species in Korea, and determined the relationship between the frequency of antifungal-resistant Candida BSI isolates and antifungal use at hospitals. Four hundred and fifty BSI isolates of Candida species were collected over a 1-year period in 2011 from nine hospitals. The susceptibilities of the isolates to four antifungal agents were determined using the CLSI M27 broth microdilution method. By applying the species-specific CBPs, non-susceptibility to fluconazole was found in 16.4% (70/428) of isolates, comprising 2.6% resistant and 13.8% susceptible-dose dependent isolates. However, non-susceptibility to voriconazole, caspofungin, or micafungin was found in 0% (0/370), 0% (0/437), or 0.5% (2/437) of the Candida BSI isolates, respectively. Of the 450 isolates, 72 (16.0%) showed decreased susceptibility to fluconazole [minimum inhibitory concentration (MIC) ≥4 μg/ml]. The total usage of systemic antifungals varied considerably among the hospitals, ranging from 190.0 to 7.7 defined daily dose per 1,000 patient days, and fluconazole was the most commonly prescribed agent (46.3%). By Spearman's correlation analysis, fluconazole usage did not show a significant correlation with the percentage of fluconazole resistant isolates at hospitals. However, fluconazole usage was significantly correlated with the percentage of fluconazole non-susceptible isolates (r = 0.733; P = 0.025) or the percentage of isolates with decreased susceptibility to fluconazole (MIC ≥4 μg/ml) (r = 0.700; P = 0.036) at hospitals. Our work represents the first South Korean multicenter study demonstrating an association between antifungal use and antifungal resistance among BSI isolates of Candida at hospitals using the new CBPs of the CLSI.

  2. Antifungal Susceptibility Profiles of Bloodstream Yeast Isolates by Sensititre YeastOne over Nine Years at a Large Italian Teaching Hospital

    PubMed Central

    Posteraro, Brunella; Spanu, Teresa; Fiori, Barbara; De Maio, Flavio; De Carolis, Elena; Giaquinto, Alessia; Prete, Valentina; De Angelis, Giulia; Torelli, Riccardo; D'Inzeo, Tiziana; Vella, Antonietta; De Luca, Alessio; Tumbarello, Mario; Ricciardi, Walter

    2015-01-01

    Sensititre YeastOne (SYO) is an affordable alternative to the Clinical and Laboratory Standards Institute (CLSI) reference method for antifungal susceptibility testing. In this study, the MICs of yeast isolates from 1,214 bloodstream infection episodes, generated by SYO during hospital laboratory activity (January 2005 to December 2013), were reanalyzed using current CLSI clinical breakpoints/epidemiological cutoff values to assign susceptibility (or the wild-type [WT] phenotype) to systemic antifungal agents. Excluding Candida albicans (57.4% of all isolates [n = 1,250]), the most predominant species were Candida parapsilosis complex (20.9%), Candida tropicalis (8.2%), Candida glabrata (6.4%), Candida guilliermondii (1.6%), and Candida krusei (1.3%). Among the non-Candida species (1.9%), 7 were Cryptococcus neoformans and 17 were other species, mainly Rhodotorula species. Over 97% of Candida isolates were susceptible (WT phenotype) to amphotericin B and flucytosine. Rates of susceptibility (WT phenotype) to fluconazole, itraconazole, and voriconazole were 98.7% in C. albicans, 92.3% in the C. parapsilosis complex, 96.1% in C. tropicalis, 92.5% in C. glabrata, 100% in C. guilliermondii, and 100% (excluding fluconazole) in C. krusei. The fluconazole-resistant isolates consisted of 6 C. parapsilosis complex isolates, 3 C. glabrata isolates, 2 C. albicans isolates, 2 C. tropicalis isolates, and 1 Candida lusitaniae isolate. Of the non-Candida isolates, 2 C. neoformans isolates had the non-WT phenotype for susceptibility to fluconazole, whereas Rhodotorula isolates had elevated azole MICs. Overall, 99.7% to 99.8% of Candida isolates were susceptible (WT phenotype) to echinocandins, but 3 isolates were nonsusceptible (either intermediate or resistant) to caspofungin (C. albicans, C. guilliermondii, and C. krusei), anidulafungin (C. albicans and C. guilliermondii), and micafungin (C. albicans). However, when the intrinsically resistant non-Candida isolates were included

  3. Synthesis and antifungal activity of 6-arylamino-phthalazine-5,8-diones and 6,7-bis(arylthio)-phthalazine-5,8-diones.

    PubMed

    Ryu, Chung-Kyu; Park, Rae-Eun; Ma, Mi-Young; Nho, Ji-Hee

    2007-05-01

    6-Arylamino-phthalazine-5,8-diones and 6,7-bis(arylthio)-phthalazine-5,8-diones were synthesized and tested for in vitro antifungal activity against two pathogenic strains of fungi. Among those tested, many compounds showed good antifungal activity. The results suggest that phthalazine-5,8-diones would be potent antifungal agents.

  4. Impact of Absolute Stereochemistry on the Antiangiogenic and Antifungal Activities of Itraconazole

    PubMed Central

    2010-01-01

    Itraconazole is used clinically as an antifungal agent and has recently been shown to possess antiangiogenic acitivity. Itraconazole has three chiral centers that give rise to eight stereoisomers. The complete role of stereochemistry in the two activities of itraconazole, however, has not been addressed adequately. For the first time, all eight stereoisomers of itraconazole (1a−h) have been synthesized and evaluated for activity against human endothelial cell proliferation and for antifungal activity against five fungal strains. Distinct antiangiogenic and antifungal activity profiles of the trans stereoisomers, especially 1e and 1f, suggest different molecular mechanisms underlying the antiangiogenic and antifungal activities of itraconazole. PMID:21892383

  5. In vitro antifungal activity and mechanism of essential oil from fennel (Foeniculum vulgare L.) on dermatophyte species.

    PubMed

    Zeng, Hong; Chen, Xinping; Liang, Jingnan

    2015-01-01

    Fennel seed essential oil (FSEO) is a plant-derived natural therapeutic against dermatophytes. In this study, the antifungal effects of FSEO were investigated from varied aspects, such as MIC and minimum fungicidal concentration, mycelia growth, spore germination and biomass. The results indicated that FSEO had potent antifungal activities on Trichophyton rubrum ATCC 40051, Trichophyton tonsurans 10-0400, Microsporum gypseum 44693-1 and Trichophyton mentagrophytes 10-0060, which is better than the commonly used antifungal agents fluconazole and amphotericin B. Flow cytometry and transmission electron microscopy experiments suggested that the antifungal mechanism of FSEO was to damage the plasma membrane and intracellular organelles. Further study revealed that it could also inhibit the mitochondrial enzyme activities, such as succinate dehydrogenase, malate dehydrogenase and ATPase. With better antifungal activity than the commonly used antifungal agents and less possibility of inducing drug resistance, FSEO could be used as a potential antidermatophytic agent.

  6. New targets and delivery systems for antifungal therapy.

    PubMed

    Walsh, T J; Viviani, M A; Arathoon, E; Chiou, C; Ghannoum, M; Groll, A H; Odds, F C

    2000-01-01

    Development of new approaches for treatment of invasive fungal infections encompasses new delivery systems for approved and investigational compounds, as well as exploiting the cell membrane, cell wall and virulence factors as putative antifungal targets. Novel delivery systems consisting of cyclodextrins, cochleates, nanoparticles/nanospheres and long circulating ('stealth') liposomes, substantially modulate the pharmacokinetics of existing compounds, and may also be useful to enhance the delivery of antifungal agents to sites of infection. Further insights into the structure-activity relationship of the antifungal triazoles that target the biosynthesis of ergosterol in the fungal cell membrane have led to the development of highly potent broad spectrum agents, including posaconazole, ravuconazole and voriconazole. Similarly, a novel generation of cell-wall active semisynthetic echinocandin 1,3 beta-glucan inhibitors (caspofungin, FK463, and VER-002) has entered clinical development. These agents have potent and broad-spectrum activity against Candida spp, and potentially useful activity against Aspergillus spp. and Pneumocystis carinii. The ongoing convergence of the fields of molecular pathogenesis, antifungal pharmacology and vaccine development will afford the opportunity to develop novel targets to complement the existing antifungal armamentarium.

  7. Epidemiological cutoff values for azoles and Aspergillus fumigatus based on a novel mathematical approach incorporating cyp51A sequence analysis.

    PubMed

    Meletiadis, J; Mavridou, E; Melchers, W J G; Mouton, J W; Verweij, P E

    2012-05-01

    Epidemiological cutoff values (ECV) are commonly used to separate wild-type isolates from isolates with reduced susceptibility to antifungal drugs, thus setting the foundation for establishing clinical breakpoints for Aspergillus fumigatus. However, ECVs are usually determined by eye, a method which lacks objectivity, sensitivity, and statistical robustness and may be difficult, in particular, for extended and complex MIC distributions. We therefore describe and evaluate a statistical method of MIC distribution analysis for posaconazole, itraconazole, and voriconazole for 296 A. fumigatus isolates utilizing nonlinear regression analysis, the normal plot technique, and recursive partitioning analysis incorporating cyp51A sequence data. MICs were determined by using the CLSI M38-A2 protocol (CLSI, CLSI document M38-A2, 2008) after incubation of the isolates for 48 h and were transformed into log(2) MICs. We found a wide distribution of MICs of all azoles, some ranging from 0.02 to 128 mg/liter, with median MICs of 32 mg/liter for itraconazole, 4 mg/liter for voriconazole, and 0.5 mg/liter for posaconazole. Of the isolates, 65% (192 of 296) had mutations in the cyp51A gene, and the majority of the mutants (90%) harbored tandem repeats in the promoter region combined with mutations in the cyp51A coding region. MIC distributions deviated significantly from normal distribution (D'Agostino-Pearson omnibus normality test P value, <0.001), and they were better described with a model of the sum of two Gaussian distributions (R(2), 0.91 to 0.96). The normal plot technique revealed a mixture of two populations of MICs separated by MICs of 1 mg/liter for itraconazole, 1 mg/liter for voriconazole, and 0.125 mg/liter for posaconazole. Recursive partitioning analysis confirmed these ECVs, since the proportions of isolates harboring cyp51A mutations associated with azole resistance were less than 20%, 20 to 30%, and >70% when the MICs were lower than, equal to, and higher than the

  8. In vitro screening of 10 edible thai plants for potential antifungal properties.

    PubMed

    Suwanmanee, Supattra; Kitisin, Thitinan; Luplertlop, Natthanej

    2014-01-01

    Growing rates of fungal infections and increasing resistance against standard antifungal drugs can cause serious health problems. There is, therefore, increasing interest in the potential use of medicinal plants as novel antifungal agents. This study investigates the antifungal properties of crude plant extracts from ten medicinal plant species. Crude samples were extracted using the hot water extraction process. The minimum inhibitory concentrations (MIC) and diameter zone of inhibition were determined in each extract against ten fungal strains, and fluconazole was used as a positive control. The cytotoxicity of crude extracts on in vitro human skin fibroblast (HSF) cell models was determined by MTT assay. Of the ten crude extracts, Psidium guajava L. exhibited the highest antifungal activity, diameter zone of inhibition, and percentage HSF cell viability. Although all extracts exhibited antifungal activity, Psidium guajava L. had the greatest potential for developing antifungal treatments.

  9. Resistance in human pathogenic yeasts and filamentous fungi: prevalence, underlying molecular mechanisms and link to the use of antifungals in humans and the environment.

    PubMed

    Jensen, Rasmus Hare

    2016-10-01

    Antifungal drug resistance is a multifaceted clinical challenge, and when present, a primary cause of treatment failure in patients with severe fungal infections. Changing epidemiology, increasing resistance rates and a narrow antifungal armamentarium may further underline the required attention on resistance particularly within the most prevalent invasive fungal infections caused by Candida yeasts and Aspergillus moulds. In Denmark, the resistance epidemiology remains to be fully elucidated. This thesis sought to address this demand as well as provide insight into the landscape of underlying molecular resistance mechanisms. Paper I and II both contributed to the understanding of FKS (β-glucan synthase) mediated echinocandin resistance in Candida species. Paper I covered a unique stepwise acquisition of a homozygous mutation in FKS1 of Candida tropicalis leading to an amino acid change corresponding to a well-known S645P in Candida albicans. Paper II presented a failure case due to Candida krusei displaying high-level echinocandin resistance likely attributable to an acquired D662Y amino acid substitution in FKS1. Intrinsic differences in FKS1 among Candida species may explain why the level of resistance both depends on the mutation as well as the species and cannot be easily translated to the level of clinical resistance. Intrinsic fluconazole resistance in C. krusei further substantiated the clinical implications of acquired echinocandin resistance. Paper III presented a rare multidrug resistance case in a series of isogenic C. albicans isolates, almost covering the entire spectrum of known resistance mechanisms in Candida and involved the proposal of novel resistance mutations. An A61E change in ERG11 was potentially involved in reduced susceptibility to long-structured azoles. Increased expression levels of azole efflux pumps were probably accredited to novel gain-of-function variants in the transcription factor TAC1 (R688Q and R673L). Echinocandin resistance

  10. Antifungal susceptibility testing.

    PubMed Central

    Rex, J H; Pfaller, M A; Rinaldi, M G; Polak, A; Galgiani, J N

    1993-01-01

    Unlike antibacterial susceptibility testing, reliable antifungal susceptibility testing is still largely in its infancy. Many methods have been described, but they produce widely discrepant results unless such factors as pH, inoculum size, medium formulation, incubation time, and incubation temperature are carefully controlled. Even when laboratories agree upon a common method, interlaboratory agreement may be poor. As a result of numerous collaborative projects carried out both independently and under the aegis of the Subcommittee on Antifungal Susceptibility Testing of the National Committee for Clinical Laboratory Standards, the effects of varying these factors have been extensively studied and a standard method which minimizes interlaboratory variability during the testing of Candida spp. and Cryptococcus neoformans has been proposed. This review summarizes this work, reviews the strengths and weaknesses of the proposed susceptibility testing standard, and identifies directions for future work. PMID:8269392

  11. Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis

    PubMed Central

    Scorzoni, Liliana; de Paula e Silva, Ana C. A.; Marcos, Caroline M.; Assato, Patrícia A.; de Melo, Wanessa C. M. A.; de Oliveira, Haroldo C.; Costa-Orlandi, Caroline B.; Mendes-Giannini, Maria J. S.; Fusco-Almeida, Ana M.

    2017-01-01

    The high rates of morbidity and mortality caused by fungal infections are associated with the current limited antifungal arsenal and the high toxicity of the compounds. Additionally, identifying novel drug targets is challenging because there are many similarities between fungal and human cells. The most common antifungal targets include fungal RNA synthesis and cell wall and membrane components, though new antifungal targets are being investigated. Nonetheless, fungi have developed resistance mechanisms, such as overexpression of efflux pump proteins and biofilm formation, emphasizing the importance of understanding these mechanisms. To address these problems, different approaches to preventing and treating fungal diseases are described in this review, with a focus on the resistance mechanisms of fungi, with the goal of developing efficient strategies to overcoming and preventing resistance as well as new advances in antifungal therapy. Due to the limited antifungal arsenal, researchers have sought to improve treatment via different approaches, and the synergistic effect obtained by the combination of antifungals contributes to reducing toxicity and could be an alternative for treatment. Another important issue is the development of new formulations for antifungal agents, and interest in nanoparticles as new types of carriers of antifungal drugs has increased. In addition, modifications to the chemical structures of traditional antifungals have improved their activity and pharmacokinetic parameters. Moreover, a different approach to preventing and treating fungal diseases is immunotherapy, which involves different mechanisms, such as vaccines, activation of the immune response and inducing the production of host antimicrobial molecules. Finally, the use of a mini-host has been encouraging for in vivo testing because these animal models demonstrate a good correlation with the mammalian model; they also increase the speediness of as well as facilitate the

  12. Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis.

    PubMed

    Scorzoni, Liliana; de Paula E Silva, Ana C A; Marcos, Caroline M; Assato, Patrícia A; de Melo, Wanessa C M A; de Oliveira, Haroldo C; Costa-Orlandi, Caroline B; Mendes-Giannini, Maria J S; Fusco-Almeida, Ana M

    2017-01-01

    The high rates of morbidity and mortality caused by fungal infections are associated with the current limited antifungal arsenal and the high toxicity of the compounds. Additionally, identifying novel drug targets is challenging because there are many similarities between fungal and human cells. The most common antifungal targets include fungal RNA synthesis and cell wall and membrane components, though new antifungal targets are being investigated. Nonetheless, fungi have developed resistance mechanisms, such as overexpression of efflux pump proteins and biofilm formation, emphasizing the importance of understanding these mechanisms. To address these problems, different approaches to preventing and treating fungal diseases are described in this review, with a focus on the resistance mechanisms of fungi, with the goal of developing efficient strategies to overcoming and preventing resistance as well as new advances in antifungal therapy. Due to the limited antifungal arsenal, researchers have sought to improve treatment via different approaches, and the synergistic effect obtained by the combination of antifungals contributes to reducing toxicity and could be an alternative for treatment. Another important issue is the development of new formulations for antifungal agents, and interest in nanoparticles as new types of carriers of antifungal drugs has increased. In addition, modifications to the chemical structures of traditional antifungals have improved their activity and pharmacokinetic parameters. Moreover, a different approach to preventing and treating fungal diseases is immunotherapy, which involves different mechanisms, such as vaccines, activation of the immune response and inducing the production of host antimicrobial molecules. Finally, the use of a mini-host has been encouraging for in vivo testing because these animal models demonstrate a good correlation with the mammalian model; they also increase the speediness of as well as facilitate the

  13. EUCAST breakpoints for antifungals.

    PubMed

    Rodríguez-Tudela, Juan L; Arendrup, Maiken C; Cuenca-Estrella, Manuel; Donnelly, J Peter; Lass-Flörl, Cornelia

    2010-03-01

    Susceptibility testing of fungi and development of interpretative breakpoints has become increasingly important due to the growing incidence of invasive fungal infections, the number and classes of antifungals, and the emerging reports of acquired resistance. The subcommittee on antifungal susceptibility testing of the European Committee on Antibiotic Susceptibility Testing (EUCAST) has developed standards for susceptibility testing of fermentative yeasts and molds as well as proposing breakpoints for fluconazole and voriconazole against Candida. The aim of this work is to describe the EUCAST process of setting breakpoints for antifungals. Five aspects are evaluated during the process of developing breakpoints: 1) the most common dosage used in each European country, 2) the definition of the wild-type population for each target microorganism at the species level and the determination of epidemiological cutoffs, 3) the drug's pharmacokinetics and 4) pharmacodynamics, including Monte Carlo simulations, and 5) the correlation of MICs with clinical outcome of patients treated with the compound. When insufficient data are available (e.g., due to lack of information on the clinical outcome of infections caused by isolates with an elevated MIC), epidemiological cutoff values, rather than breakpoints, are recommended until the necessary information becomes available.

  14. Synthesis of new 5-((2-(substituted phenoxymethyl)-1H-benzo[d]imidazol-1-yl)methyl)-1,3,4-oxadiazole-2-thiol: A novel class of potential antibacterial and antifungal agents.

    PubMed

    Manjunath, G; Bheemaraju, G; Mahesh, M; Venkata Ramana, P

    2015-11-01

    Novel 1,3,4-Oxadiazoles bearing benzimidazole nucleus were designed, synthesized using 2-(2-(substituted phenoxymethyl)-1H-benzo[d]imidazol-1-yl)acetohydrazide and carbon disulfide. These newly synthesized benzimidazolyl oxadiazoles along with benzimidazolyl acetates and benzimidazolyl acetohydrazides were screened for their antibacterial activity against two kinds of strains using the agar disk diffusion method and antifungal activity against Aspergillus niger and Ustilago maydis. The results showed that some of the compounds exhibited moderate activity against both the strains in antibacterial activity and majority of compounds are not active in antifungal activity. The structure-activity relationships were briefly discussed. The studies indicated that compounds of Benzimidazolyl acetohydrazide were the most potent inhibitors compared to the other compounds under investigation.

  15. IPC synthase as a useful target for antifungal drugs.

    PubMed

    Sugimoto, Yuichi; Sakoh, Hiroki; Yamada, Koji

    2004-12-01

    Inositol phosphorylceramide (IPC) synthase is a common and essential enzyme in fungi and plants, which catalyzes the transfer of phosphoinositol to the C-1 hydroxy of ceramide to produce IPC. This reaction is a key step in fungal sphingolipid biosynthesis, therefore the enzyme is a potential target for the development of nontoxic therapeutic antifungal agents. Natural products with a desired biological activity, aureobasidin A (AbA), khafrefungin, and galbonolide A, have been reported. AbA, a cyclic depsipeptide containing 8 amino acids and a hydroxyl acid, is a broad spectrum antifungal with strong activity against many pathogenic fungi such as Candida spp., Cryptococcus neoformans, and some Aspergillus spp. Khafrefungin, an aldonic acid ester with a C22 long alkyl chain, has antifungal activity against C. albicans, Cr. Neoformans, and Saccharomyces cerevisiae. Galbonolide A is a 14-membered macrolide with fungicidal activity against clinically important strains, and is especially potent against Cr. neoformans. These classes of natural products are potent and specific antifungal agents. We review current progress in the development of IPC synthase inhibitors with antifungal activities, and present structure-activity relationships (SAR), physicochemical and structural properties, and synthetic methodology for chemical modification.

  16. Antifungal ellagitannin isolated from Euphorbia antisyphilitica Zucc

    PubMed Central

    Ascacio-Valdés, Juan; Burboa, Edgardo; Aguilera-Carbo, Antonio F; Aparicio, Mario; Pérez-Schmidt, Ramón; Rodríguez, Raúl; Aguilar, Cristóbal N

    2013-01-01

    Objective To study antifungal activity of a new ellagitannin isolated from the plant residues of Euphorbia antisyphilitica (E. antisyphilitica) Zucc in the wax extraction process. Methods An extract was prepared from dehydrated and pulverized residues and fractionated by liquid chromatography on Amberilte XAD-16, until obtained an ellagitannin-rich ethanolic fraction which was treated by rotaevaporation to recover the ellagitannin as fine powder. An aqueous solution was prepared and treated through ionic exchange liquid chromatography (Q XL) and gel permeation chromatography (G 25). The ellagitannin-rich fraction was thermogravimetrically evaluated (TGA and DTA) to test the thermo-stability of ellagic acid (monomeric unit). Then ellagitannin powder was analyzed by infrared spectrospcopy to determinate the functional groups and, also mass spectroscopy was used to determine the molecular ion. Results The principal functional groups of ellagitannin were determined, the molecular weight was 860.7 g/mol; and an effective antifungal activity against phytopathogenic fungi was demonstrated. Conclusions It can be concluded that the new ellagitannin (860.7 g/mol) isolated from E. antisyphilitica Zucc is an effective antifungal agent against Alternaria alternata, Fusarium oxyzporum, Colletotrichum gloeosporoides and Rhizoctnia solani. PMID:23570015

  17. Azole susceptibility of Malassezia pachydermatis and Malassezia furfur and tentative epidemiological cut-off values.

    PubMed

    Cafarchia, Claudia; Iatta, Roberta; Immediato, Davide; Puttilli, Maria Rita; Otranto, Domenico

    2015-09-01

    This study aims to determine the minimal inhibitory concentration (MIC) distribution and the epidemiological cut-off values (ECVs) of Malassezia pachydermatis and Malassezia furfur isolates for fluconazole (FLZ), itraconazole (ITZ), posaconazole (POS), and voriconazole (VOR). A total of 62 M. pachydermatis strains from dogs with dermatitis and 78 M. furfur strains from humans with bloodstream infections (BSI) were tested by a modified broth microdilution Clinical and Laboratory Standards Institute (CLSI) method. ITZ and POS displayed lower MICs than VOR and FLZ, regardless of the Malassezia species. The MIC data for azoles of M. pachydermatis were four two-fold dilutions lower than those of M. furfur. Based on the ECVs, about 94% of Malassezia strains might be categorized within susceptible population for all azoles, except for FLZ, and azole cross-resistance was detected in association with FLZ in M. pachydermatis but not in M. furfur.The study proposes, for the first time, tentative azole ECVs for M. pachydermatis and M. furfur for monitoring the emergence of isolates with decreased susceptibilities and shows that the azole MIC distribution varied according to the Malassezia species tested, thus suggesting the usefulness of determining the susceptibility profile for effective treatment of each species.

  18. Antifungal adjuvants: Preserving and extending the antifungal arsenal.

    PubMed

    Butts, Arielle; Palmer, Glen E; Rogers, P David

    2017-02-17

    As the rates of systemic fungal infections continue to rise and antifungal drug resistance becomes more prevalent, there is an urgent need for new therapeutic options. This issue is exacerbated by the limited number of systemic antifungal drug classes. However, the discovery, development, and approval of novel antifungals is an extensive process that often takes decades. For this reason, there is growing interest and research into the possibility of combining existing therapies with various adjuvants that either enhance activity or overcome existing mechanisms of resistance. Reports of antifungal adjuvants range from plant extracts to repurposed compounds, to synthetic peptides. This approach would potentially prolong the utility of currently approved antifungals and mitigate the ongoing development of resistance.

  19. In vitro antifungal susceptibility of Cryptococcus gattii.

    PubMed

    Trilles, Luciana; Fernández-Torres, Belkys; Lazéra, Márcia dos Santos; Wanke, Bodo; Guarro, Josep

    2004-10-01

    We have determined the in vitro susceptibilities of 57 strains of Cryptococcus gattii to nine antifungal agents and have compared the MICs for these strains with those for C. neoformans. MICs were determined by a microdilution reference method. Albaconazole and ravuconazole (MICs of 0.04 and 0.05 microg/ml, respectively) showed the best activities. Micafungin showed no activity (MIC of >128 microg/ml). In general, C. gattii was less susceptible than C. neoformans to all drugs tested, with the exception of amphotericin B and flucytosine.

  20. Progress in antibacterial and antifungal chemotherapy.

    PubMed

    Fromtling, R A

    2000-08-01

    The European Society of Clinical Microbiology and Infectious Diseases sponsored the 10th European Congress on Clinical Microbiology and Infectious Diseases in Stockholm, Sweden, May 28-31, 2000. At the ECMID, well-attended sessions were held which focused on the pathogenesis and therapy of viral, bacterial and fungal diseases. This report focuses on new information on resistance to antibacterial agents, including data from recent surveillance studies, and the in vitro and investigational clinical activity of new antibacterial (moxifloxacin, telithromycin) and antifungal (fluconazole, itraconazole, voriconazole, amphotericin B, liposomal formulations of amphotericin B, terbinafine and the candins) drugs.

  1. In Vitro Antifungal Susceptibility of Cryptococcus gattii

    PubMed Central

    Trilles, Luciana; Fernández-Torres, Belkys; dos Santos Lazéra, Márcia; Wanke, Bodo; Guarro, Josep

    2004-01-01

    We have determined the in vitro susceptibilities of 57 strains of Cryptococcus gattii to nine antifungal agents and have compared the MICs for these strains with those for C. neoformans. MICs were determined by a microdilution reference method. Albaconazole and ravuconazole (MICs of 0.04 and 0.05 μg/ml, respectively) showed the best activities. Micafungin showed no activity (MIC of >128 μg/ml). In general, C. gattii was less susceptible than C. neoformans to all drugs tested, with the exception of amphotericin B and flucytosine. PMID:15472349

  2. Chemical modification of antifungal polyene macrolide antibiotics

    NASA Astrophysics Data System (ADS)

    Solovieva, S. E.; Olsufyeva, E. N.; Preobrazhenskaya, M. N.

    2011-02-01

    The review summarizes advances in the methods for the synthesis of polyene antibiotics (amphotericin B, partricin A, etc.) and investigations of the structure-activity relationship made in the last 15 years. State-of-the-art approaches based on the combination of the chemical synthesis and genetic engineering are considered. Emphasis is given to the design of semisynthetic antifungal agents against chemotherapy-resistant pathogens having the highest therapeutic indices. Recent results of research on the mechanisms of action of polyenes are outlined.

  3. Terconazole - a new broad-spectrum antifungal.

    PubMed

    Van Cutsem, J; Van Gerven, F; Zaman, R; Janssen, P A

    1983-01-01

    Terconazole, a new triazole ketal, is found to be highly active in vitro on a wide range of yeasts and mycelium-forming fungi. The in vitro activity depends largely on the medium used. In vitro it is a potent antifungal agent in preventing the morphogenetic transformation of the yeast into the (pseudo-)mycelium form of Candida albicans. In vivo terconazole is highly active in topical treatment of various experimental models of dermatophytosis and candidosis. It also possesses moderate oral broad-spectrum activity. No side effects were observed.

  4. [In vitro antifungal resistance in Candida albicans from HIV-infected patients with and without oral candidosis.].

    PubMed

    Ceballos Salobreña, A; Gaitán Cepeda, L A; Orihuela Cañada, F; Olea Barrionuevo, D; Ceballos García, L; Quindós, G

    1999-12-01

    The main purpose of this study has been to determine the in vitro antifungal susceptibility of clinical isolates from HIV-infected or AIDS patients, depending on the presence of oral candidosis. The oral cavity of 307 HIV-infected or AIDS patients was examined and an oral swab was cultured on Sabouraud glucose agar and studied by conventional mycological methods. In vitro antifungal susceptibility to amphotericin B, nystatin, fluconazole, itraconazole and ketoconazole was tested by disk diffusion with Neo-Sensitabs tablets (Rosco Diagnostica, Dinamarca). One hundred and thirty five Candida albicans isolates (91 serotype A, 38 serotype B, three C. albicans variety stellatoidea and three untyped isolates), three Candida krusei and two Candida glabrata were obtained. All the isolates were susceptible to nystatin and amphotericin B. However, 7.9% isolates were resistant to fluconazole and 2.9% isolates were resistant to ketoconazole or itraconazole. Nearly all C. krusei and C. glabrata isolates, 31% patients with candidosis and 20% Candida-colonized patients showed decreased susceptibility to azoles. This study shows that polyenes had a great in vitro efficacy against clinical isolates from HIV-infected patients and that in vitro resistance to azoles is not as high as observed in other countries.

  5. Caenorhabditis elegans-based Model Systems for Antifungal Drug Discovery

    PubMed Central

    Anastassopoulou, Cleo G.; Fuchs, Beth Burgwyn; Mylonakis, Eleftherios

    2013-01-01

    The substantial morbidity and mortality associated with invasive fungal infections constitute undisputed tokens of their severity. The continued expansion of susceptible population groups (such as immunocompromised individuals, patients undergoing extensive surgery, and those hospitalized with serious underlying diseases especially in the intensive care unit) and the limitations of current antifungal agents due to toxicity issues or to the development of resistance, mandate the development of novel antifungal drugs. Currently, drug discovery is transitioning from the traditional in vitro large-scale screens of chemical libraries to more complex bioassays, including in vivo studies on whole animals; invertebrates, such as Caenorhabditis elegans, are thus gaining momentum as screening tools. Key pathogenesis features of fungal infections, including filament formation, are expressed in certain invertebrate and mammalian hosts; among the various potential hosts, C. elegans provides an attractive platform both for the study of host-pathogen interactions and the identification of new antifungal agents. Advantages of compound screening in this facile, relatively inexpensive and not as ethically challenged whole-animal context, include the simultaneous assessment of antifungal efficacy and toxicity that could result in the identification of compounds with distinct mechanisms of action, for example by promoting host immune responses or by impeding fungal virulence factors. With the recent advent of using predictive models to screen for compounds with improved chances of bioavailability in the nematode a priori, high-throughput screening of chemical libraries using the C. elegans-c. albicans antifungal discovery assay holds even greater promise for the identification of novel antifungal agents in the near future. PMID:21470110

  6. Susceptibility of Sporothrix brasiliensis isolates to amphotericin B, azoles, and terbinafine.

    PubMed

    Borba-Santos, Luana Pereira; Rodrigues, Anderson Messias; Gagini, Thalita Braga; Fernandes, Geisa Ferreira; Castro, Rafaela; de Camargo, Zoilo Pires; Nucci, Marcio; Lopes-Bezerra, Leila Maria; Ishida, Kelly; Rozental, Sonia

    2015-02-01

    The in vitro activity of the antifungal agents amphotericin B (AMB), itraconazole (ITC), posaconazole (PSC), voriconazole (VRC), and terbinafine (TRB) against 32 Brazilian isolates of Sporothrix brasiliensis, including 16 isolates from a recent (2011-2012) epidemic in Rio de Janeiro state, was examined. We describe and genotype new isolates and clustered them with 16 older (from 2004 or earlier) S. brasiliensis isolates by phylogenetic analysis. We tested both the yeast and the mycelium form of all isolates using broth microdilution methods based on the reference protocols M38-A2 and M27-A3 (recommended by the Clinical and Laboratory Standards Institute). Considering minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs), TRB was found to be the most active drug in vitro for both fungal forms, followed by PSC. Several isolates showed high MICs for AMB and/or ITC, which are currently used as first-line therapy for sporotrichosis. VRC displayed very low activity against S. brasiliensis isolates. The primary morphological modification observed on treated yeasts by transmission electron microscopy analysis was changes in cell wall. Our results indicate that TRB is the antifungal with the best in vitro activity against S. brasiliensis and support the use of TRB as a promising option for the treatment of cutaneous and/or lymphocutaneous sporotrichosis.

  7. A study to evaluate the price control of antifungal medicines and its practical applicability

    PubMed Central

    Sil, Amrita; Das, Nilay Kanti; Ghosh, Pramit; Datta, Pijush Kanti; Islam, Chowdhury Nazrul; Tripathi, Santanu Kumar

    2012-01-01

    Background: Superficial fungal infections are common and treatment imposes economic burden on the patients. Government of India had introduced price control over griseofulvin and tolnaftate in 1995; however, this measure can only benefit the needy if the policy is harmonized with the health-care service provider, that is, dermatologists. The aim of this study was to evaluate the existing Government mechanisms over price control of antifungal medications and its reach to the people-in-need. Materials and Methods: A questionnaire-based, cross-sectional study was carried out over a period of 6 months. Questionnaire was mailed to members of a state branch of Indian Association of Dermatologists, Venereologists, and Leprologists. Responses reaching investigators within 2 months from the date of mailing were finally analyzed. Results: Among 93 (41.33%) respondents, only 6 (6.5%) were aware of existing price control over griseofulvin but none about tolnaftate. Thirty-nine (41.9%) respondents were in favor of introducing price control on terbinafine and 42 (45.2%) for itraconazole. The topically preferred antifungals were primarily azoles and terbinafine, while among systemic antifungals, dermatologists mostly preferred fluconazole and terbinafine. The choice of antifungals by the dermatologists matched with the evidence-based dermatology data. Conclusion: Currently, price-controlled antifungal drugs are less commonly used by practitioners. Although the dermatologists favor price control, the initiative undertaken by the Government has not reached them. This shows the need to bridge the gap between policy makers and health-care service providers to help the ailing population. PMID:23248398

  8. Antifungal activity of Brevibacillus laterosporus JX-5 and characterization of its antifungal components.

    PubMed

    Jiang, Hongxia; Wang, Xiaohui; Xiao, Chengze; Wang, Weiyan; Zhao, Xu; Sui, Junkang; Sa, Rongbo; Guo, Tai L; Liu, Xunli

    2015-10-01

    The establishment of safe and effective methods for controlling fungal disease is an urgent issue in agriculture and forestry. Microbiological control of plant disease is expected to achieve better results than use of chemically derived fungicides. This study aimed to establish Brevibacillus laterosporus JX-5 as a potential microbiological control agent of poplar canker. The bacterium was isolated from the poplar rhizosphere and demonstrated significant growth inhibition of several pathogenic fungi in vitro. The antifungal components of Br. laterosporus JX-5 were isolated and identified. The fermentation broth of Br. laterosporus JX-5 and its main antifungal component, designated as component B, reduced Botryosphaeria dothidea associated canker of the excised poplar branch by 70 and 90%, respectively. Component B is considerably heat-stable, adaptable to a broad pH range, and UV-resistant. It could inhibit Bo. dothidea by permeating the fungal membrane, fracturing the nuclei, damaging the cell wall, and eventually killing the pathogenic fungus. The antifungal activity exhibited by Br. laterosporus JX-5 and its bioactive metabolic products indicate its feasibility as a potential biocontrol agent for plant diseases.

  9. Exogenous tyrosol inhibits planktonic cells and biofilms of Candida species and enhances their susceptibility to antifungals.

    PubMed

    Cordeiro, Rossana de A; Teixeira, Carlos E C; Brilhante, Raimunda S N; Castelo-Branco, Débora S C M; Alencar, Lucas P; de Oliveira, Jonathas S; Monteiro, André J; Bandeira, Tereza J P G; Sidrim, José J C; Moreira, José Luciano Bezerra; Rocha, Marcos F G

    2015-06-01

    Tyrosol is a quorum-sensing molecule of Candida albicans able to induce hyphal development in the early and intermediate stages of biofilm growth. In the present study, we evaluated the effect of high concentrations of exogenous tyrosol on planktonic cells and biofilms of C. albicans (n = 10) and C. tropicalis (n = 10), and investigated whether tyrosol could be synergic to antifungals that target cellular ergosterol. Antifungal susceptibility and drug interaction against planktonic cells were investigated by the broth microdilution method. Tyrosol was able to inhibit planktonic cells, with MIC values ranging from 2.5 to 5.0 mM for both species. Synergism was observed between tyrosol/amphotericin B (11/20 strains), tyrosol/itraconazole (18/20 strains) and tyrosol/fluconazole (18/20 strains). Exogenous tyrosol alone or combined with antifungals at both 10 × MIC and 50 × MIC were able to reduce biofilm of both Candida species. Mature biofilms were susceptible to tyrosol alone at 50 × MIC or combined with amphotericin at both 10 × MIC and 50 × MIC. On the other hand, tyrosol plus azoles at both 10 × MIC and 50 × MIC enhanced biofilm growth.

  10. Penetration of new azole compounds into the eye and efficacy in experimental Candida endophthalmitis.

    PubMed Central

    Savani, D V; Perfect, J R; Cobo, L M; Durack, D T

    1987-01-01

    We studied the penetration of three azole compounds, ketoconazole, itraconazole, and fluconazole, into the ocular tissues and fluids of rabbits in the presence and absence of ocular inflammation. Drug concentrations were compared with those found in serum and cerebrospinal fluid. The rank order of penetration into eye tissue was fluconazole greater than ketoconazole greater than itraconazole. Fluconazole penetrated freely into both inflamed and uninflamed eyes. The presence of inflammation improved penetration of all three compounds into ocular fluids and tissues. Penetration of these azoles into the anterior chamber of uninflamed eyes and into the cerebrospinal fluid was similar. All three azole compounds reduced the number of yeasts found in the eye in hematogenous Candida albicans endophthalmitis in rabbits when therapy was initiated within 24 h of inoculation. However, only ketoconazole significantly reduced yeast counts in the eye when therapy was postponed for 7 days. PMID:3032091

  11. Membrane Proteome-Wide Response to the Antifungal Drug Clotrimazole in Candida glabrata: Role of the Transcription Factor CgPdr1 and the Drug:H+ Antiporters CgTpo1_1 and CgTpo1_2.

    PubMed

    Pais, Pedro; Costa, Catarina; Pires, Carla; Shimizu, Kiminori; Chibana, Hiroji; Teixeira, Miguel C

    2016-01-01

    Azoles are widely used antifungal drugs. This family of compounds includes triazoles, mostly used in the treatment of systemic infections, and imidazoles, such as clotrimazole, often used in the case of superficial infections. Candida glabrata is the second most common cause of candidemia worldwide and presents higher levels of intrinsic azole resistance when compared with Candida albicans, thus being an interesting subject for the study of azole resistance mechanisms in fungal pathogens.Since resistance often relies on the action of membrane transporters, including drug efflux pumps from the ATP-binding cassette family or from the Drug:H(+) antiporter (DHA)(1) family, an iTRAQ-based membrane proteomics analysis was performed to identify all the membrane-associated proteins whose abundance changes in C. glabrata cells exposed to the azole drug clotrimazole. Proteins found to have significant expression changes in this context were clustered into functional groups, namely: glucose metabolism, oxidative phosphorylation, mitochondrial import, ribosome components and translation machinery, lipid metabolism, multidrug resistance transporters, cell wall assembly, and stress response, comprising a total of 37 proteins. Among these, the DHA transporter CgTpo1_2 (ORF CAGL0E03674g) was identified as overexpressed in the C. glabrata membrane in response to clotrimazole. Functional characterization of this putative drug:H(+) antiporter, and of its homolog CgTpo1_1 (ORF CAGL0G03927g), allowed the identification of these proteins as localized to the plasma membrane and conferring azole drug resistance in this fungal pathogen by actively extruding the drug to the external medium. The cell wall protein CgGas1 was also shown to confer azole drug resistance through cell wall remodeling. Finally, the transcription factor CgPdr1 in the clotrimazole response was observed to control the expression of 20 of the identified proteins, thus highlighting the existence of additional unforeseen

  12. Membrane Proteome-Wide Response to the Antifungal Drug Clotrimazole in Candida glabrata: Role of the Transcription Factor CgPdr1 and the Drug:H+ Antiporters CgTpo1_1 and CgTpo1_2*

    PubMed Central

    Pais, Pedro; Costa, Catarina; Pires, Carla; Shimizu, Kiminori; Chibana, Hiroji; Teixeira, Miguel C.

    2016-01-01

    Azoles are widely used antifungal drugs. This family of compounds includes triazoles, mostly used in the treatment of systemic infections, and imidazoles, such as clotrimazole, often used in the case of superficial infections. Candida glabrata is the second most common cause of candidemia worldwide and presents higher levels of intrinsic azole resistance when compared with Candida albicans, thus being an interesting subject for the study of azole resistance mechanisms in fungal pathogens. Since resistance often relies on the action of membrane transporters, including drug efflux pumps from the ATP-binding cassette family or from the Drug:H+ antiporter (DHA)1 family, an iTRAQ-based membrane proteomics analysis was performed to identify all the membrane-associated proteins whose abundance changes in C. glabrata cells exposed to the azole drug clotrimazole. Proteins found to have significant expression changes in this context were clustered into functional groups, namely: glucose metabolism, oxidative phosphorylation, mitochondrial import, ribosome components and translation machinery, lipid metabolism, multidrug resistance transporters, cell wall assembly, and stress response, comprising a total of 37 proteins. Among these, the DHA transporter CgTpo1_2 (ORF CAGL0E03674g) was identified as overexpressed in the C. glabrata membrane in response to clotrimazole. Functional characterization of this putative drug:H+ antiporter, and of its homolog CgTpo1_1 (ORF CAGL0G03927g), allowed the identification of these proteins as localized to the plasma membrane and conferring azole drug resistance in this fungal pathogen by actively extruding the drug to the external medium. The cell wall protein CgGas1 was also shown to confer azole drug resistance through cell wall remodeling. Finally, the transcription factor CgPdr1 in the clotrimazole response was observed to control the expression of 20 of the identified proteins, thus highlighting the existence of additional unforeseen

  13. Antifungal Drugs for Onychomycosis: Efficacy, Safety, and Mechanisms of Action.

    PubMed

    Rosen, Theodore; Stein Gold, Linda F

    2016-03-01

    In 1996, oral terbinafine joined itraconazole and fluconazole on the short list of systemic medications that could be used to treat onychomycosis (although fluconazole was not approved for this indication by the US Food and Drug Administration [FDA], it was commonly used for this purpose). In 1999, ciclopirox was the first topical treatment to be FDA approved. The addition of the topical antifungal agents efinaconazole and tavaborole in 2014 expanded the roster of medications available to more effectively manage onychomycosis in a wide range of patients, including those for whom comorbid conditions, concomitant medications, or patient preference limited the use of systemic antifungals.

  14. Imidazolylchromanones containing non-benzylic oxime ethers: synthesis and molecular modeling study of new azole antifungals selective against Cryptococcus gattii.

    PubMed

    Babazadeh-Qazijahani, Mojtaba; Badali, Hamid; Irannejad, Hamid; Afsarian, Mohammad Hosein; Emami, Saeed

    2014-04-09

    A series of imidazolylchromanone oximes containing phenoxyethyl ether moiety, as found in omoconazole, were synthesized and evaluated against yeasts (Candida albicans and Cryptococcus gattii) and filamentous fungi (Aspergillus fumigatus and Exophiala dermatitidis). Although the title compounds showed marginal activity against filamentous fungi but all of them exhibited potent activity against C. gattii (MIC values ≤4 μg/mL). Among them, (3-chlorophenoxy)ethyl analog 7c with MIC value of 0.5 μg/mL was the most potent compound. Further molecular docking studies provided a better insight into the binding of designed compounds within the homology modeled active site of CnCYP51 (Cryptococcus CYP51-14α-demethylase).

  15. nor-Mevaldic acid surrogates as selective antifungal agent leads against Botrytis cinerea. Enantioselective preparation of 4-hydroxy-6-(1-phenylethoxy)tetrahydro-2H-pyran-2-one.

    PubMed

    Botubol-Ares, José Manuel; Durán-Peña, María Jesús; Hernández-Galán, Rosario; Collado, Isidro G; Harwood, Laurence M; Macías-Sánchez, Antonio J

    2015-07-01

    Solvent-free desymmetrisation of meso-dialdehyde 1 with chiral 1-phenylethan-1-ol, led to preparation of 4-silyloxy-6-alkyloxytetrahydro-2H-pyran-2-one (+)-3a with a 96:4 dr Deprotected lactone (+)-19a and the related racemic lactones 16a-18a present a lactone moiety resembling the natural substrate of HMG-CoA reductase and their antifungal properties have been evaluated against the phytopathogenic fungi Botrytis cinerea and Colletotrichum gloeosporioides. These compounds were selectively active against B. cinerea, while inactive against C. gloeosporioides.

  16. Detection of azole susceptibility patterns in clinical yeast strains isolated from 1998 to 2008.

    PubMed

    Czaika, Viktor; Nenoff, Pietro; Glöckner, Andreas; Becker, Karsten; Fegeler, Wolfgang; Schmalreck, Arno F

    2014-10-01

    4,860 clinical yeast isolates (25 genera, 47 species) were tested in parallel to fluconazole, itraconazole, ketoconazole, and voriconazole. After re-evaluation of all species according to their current valid taxonomic denominations, the range of the top four of the dermatology, gynaecology and paediatrics associated species from superficial infections was similar to those isolated from other wards with mainly systemic/invasive infections. Candida albicans (44.7%) was the most frequent pathogen followed by C. glabrata, C. tropicalis, and C. parapsilosis. The MIC-assessment revealed for the ten-year test period an overall azole-susceptibility of about 75%, and ~80% for their associated ICUs. The overall susceptibility of the isolates from systemic and superficial infections to the four azoles was 79% and 80% respectively, and demonstrates a high in vitro activity. When two test periods (1998-2001 and 2002-2008) were compared by characteristic MIC values and multi-azole resistance, no significant increase could be detected in azole susceptibility/resistance over the two periods, respectively, over the total investigation period of ten years. This holds true when the characteristic MIC values were compared with those from different azole susceptibility studies from similar time periods and from different investigators around the world (1991 to 2010). With a new method, susceptibility pattern analysis for fungi, detailed information of multi-resistant microorganism populations could be obtained, and different characteristic resistance patterns in clinical yeast species detected. Although at a relatively low level, multi-resistance was seen in individual species populations demonstrating resistance to two (6.7%), three (4.4%), or all four (4%) azoles tested. A level of 4% and 2% fourfold parallel resistance was also determined in Candia spp. and non-Candida spp. derived of blood culture isolates.

  17. Genotyping of Fusarium Isolates from Onychomycoses in Colombia: Detection of Two New Species Within the Fusarium solani Species Complex and In Vitro Antifungal Susceptibility Testing.

    PubMed

    Guevara-Suarez, Marcela; Cano-Lira, José Francisco; de García, María Caridad Cepero; Sopo, Leticia; De Bedout, Catalina; Cano, Luz Elena; García, Ana María; Motta, Adriana; Amézquita, Adolfo; Cárdenas, Martha; Espinel-Ingroff, Ana; Guarro, Josep; Restrepo, Silvia; Celis, Adriana

    2016-04-01

    Fusariosis have been increasing in Colombia in recent years, but its epidemiology is poorly known. We have morphologically and molecularly characterized 89 isolates of Fusarium obtained between 2010 and 2012 in the cities of Bogotá and Medellín. Using a multi-locus sequence analysis of rDNA internal transcribed spacer, a fragment of the translation elongation factor 1-alpha (Tef-1α) and of the RNA-dependent polymerase subunit II (Rpb2) genes, we identified the phylogenetic species and circulating haplotypes. Since most of the isolates studied were from onychomycoses (nearly 90 %), we carried out an epidemiological study to determine the risk factors associated with such infections. Five phylogenetic species of the Fusarium solani species complex (FSSC), i.e., F. falciforme, F. keratoplasticum, F. lichenicola, F. petroliphilum, and FSSC 6 as well as two of the Fusarium oxysporum species complex (FOSC), i.e., FOSC 3 and FOSC 4, were identified. The most prevalent species were FOSC 3 (38.2%) followed by F. keratoplasticum (33.7%). In addition, our isolates were distributed into 23 haplotypes (14 into FOSC and nine into FSSC). Two of the FSSC phylogenetic species and two haplotypes of FSSC were not described before. Our results demonstrate that recipients of pedicure treatments have a lower probability of acquiring onychomycosis than those not receiving such treatments. The antifungal susceptibility of all the isolates to five clinically available agents showed that amphotericin B was the most active drug, while the azoles exhibited lower in vitro activity.

  18. In Vitro Antifungal Susceptibility Profiles of 12 Antifungal Drugs against 55 Trichophyton schoenleinii Isolates from Tinea Capitis Favosa Patients in Iran, Turkey, and China.

    PubMed

    Deng, Shuwen; Ansari, Saham; Ilkit, Macit; Rafati, Haleh; Hedayati, Mohammad T; Taghizadeh-Armaki, Mojtaba; Nasrollahi-Omran, Ayatollah; Tolooe, Ali; Zhan, Ping; Liao, Wanqing; van der Lee, Henrich A; Verweij, Paul E; Seyedmousavi, Seyedmojtaba

    2017-02-01

    Trichophyton schoenleinii is an anthropophilic dermatophyte mainly causing tinea favosa of the scalp in certain regions of the world, especially Africa and Asia. We investigated the in vitro susceptibilities of 55 T. schoenleinii isolates collected over the last 30 years from Iran, Turkey, and China to 12 antifungals using the CLSI broth microdilution method. Our results revealed that terbinafine and ketoconazole were the most potent antifungal agents among those tested, independently of the geographic regions where strains were isolated.

  19. Fungus-Elicited Metabolites from Plants as an Enriched Source for New Leishmanicidal Agents: Antifungal Phenyl-Phenalenone Phytoalexins from the Banana Plant (Musa acuminata) Target Mitochondria of Leishmania donovani Promastigotes

    PubMed Central

    Luque-Ortega, Juan Román; Martínez, Silvia; Saugar, José María; Izquierdo, Laura R.; Abad, Teresa; Luis, Javier G.; Piñero, José; Valladares, Basilio; Rivas, Luis

    2004-01-01

    Two antifungal phenyl-phenalenone phytoalexins isolated from the banana plant (Musa acuminata) elicited with the fungus Fusarium oxysporum, together with a methoxy derivative of one of them and two epoxide precursors of their chemical synthesis, were tested for leishmanicidal activity on Leishmania donovani promastigotes and L. infantum amastigotes. Drugs inhibited proliferation of both forms of the parasite with a 50% lethal concentration range between 10.3 and 68.7 μg/ml. Their lethal mechanism was found linked to the respiratory chain by a systematic approach, including electron microscopy, measurement of the oxygen consumption rate on digitonin-permeabilized promastigotes, and enzymatic assays on a mitochondrial enriched fraction. Whereas the whole set of compounds inhibited the activity of fumarate reductase in the mitochondrial fraction (50% effective concentration [EC50] between 33.3 and 78.8 μg/ml) and on purified enzyme (EC50 = 53.3 to 115 μg/ml), inhibition for succinate dehydrogenase was only observed for the two phytoalexins with the highest leishmanicidal activity: anigorufone and its natural analogue 2-methoxy-9-phenyl-phenalen-1-one (EC50 = 33.5 and 59.6 μg/ml, respectively). These results provided a new structural motif, phenyl-phenalenone, as a new lead for leishmanicidal activity, and support the use of plant extracts enriched in antifungal phytoalexins, synthesized under fungal challenge, as a more rational and effective strategy to screen for new plant leishmanicidal drugs. PMID:15105102

  20. Antifungal susceptibility against yeasts isolated from pediatric oncology patients.

    PubMed

    Kersun, L S; Reilly, A F; Ingram, M E; Nicholaou, M J; McGowan, K L

    2008-06-01

    Yeast infections cause morbidity in children with cancer and we evaluated species distribution and antifungal susceptibilities of the etiologic agents in this group. Specimens from 58 children yielded 64 cultures positive for yeasts. Central venous catheters were present in 56 (97%) of the children and neutrophil counts were <500 cells/ml3 in 34% of the patients. Twenty-two (38%) had received recent antifungal treatment, with 15 (25%) receiving fluconazole (FLU) prophylaxis. The Candida isolates recovered from four (27%) of the children on FLU prophylaxis, were resistant to this drug. Candida albicans isolates were susceptible to 100% of antifungals tested, whereas non-C. albicans Candida spp. were variable in their susceptibility patterns. FLU prophylaxis minimally affected susceptibility.

  1. Design of amphotericin B oral formulation for antifungal therapy.

    PubMed

    Liu, Min; Chen, Meiwan; Yang, Zhiwen

    2017-11-01

    Amphotericin B (AmB) remains the "gold standard" for systemic antifungal therapy, even though new drugs are emerging as the attractive antifungal agents. Since AmB has negligible oral absorption as a consequence of its unfavorable physicochemical characterizations, its use is restricted to parenteral administration which is accompanied by severe side effects. As greater understanding of the gastrointestinal tract has developed, the advanced drug delivery systems are emerging with the potential to overcome the barriers of AmB oral delivery. Much research has demonstrated that oral AmB formulations such as lipid formulations may have beneficial therapeutic efficacy with reduced adverse effects and suitable for clinical application. Here we reviewed the different formulation strategies to enhance oral drug efficacy, and discussed the current trends and future perspectives for AmB oral administration in the treatment of antifungal infections.

  2. Antifungal-protein production in maize (Zea mays) suspension cultures.

    PubMed

    Perri, Fabio; Della Penna, Serena; Rufini, Francesca; Patamia, Maria; Bonito, Mariantonietta; Angiolella, Letizia; Vitali, Alberto

    2009-04-01

    The growing emergency due to the phenomenon of drug resistance to micro-organisms has pushed forward the search for new potential drug alternatives to those already in use. Plants represent a suitable source of new antifungal molecules, as they produce a series of defensive proteins. Among them are the PRPs (pathogenesis-related proteins), shown to be effective in vitro against human pathogens. An optimized and established cell-suspension culture of maize (Zea mays) was shown to constitutively secrete in the medium a series of PRPs comprising the antifungal protein zeamatin (P33679) with a final yield of approx. 3 mg/litre. The in-vitro-produced zeamatin possessed antifungal activity towards a clinical strain of the human pathogenic yeast Candida albicans, an activity comparable with the one reported for the same protein extracted from maize seeds. Along with zeamatin, other PRPs were expressed: a 9 kDa lipid-transfer protein, a 26 kDa xylanase inhibitor and a new antifungal protein, PR-5. A fast, two-step chromatographic procedure was set up allowing the complete purification of the proteins considered, making this cell line a valuable system for the production of potential antifungal agents in a reliable and easy way.

  3. Antifungal activity of multifunctional Fe 3O 4-Ag nanocolloids

    NASA Astrophysics Data System (ADS)

    Chudasama, Bhupendra; Vala, Anjana K.; Andhariya, Nidhi; Upadhyay, R. V.; Mehta, R. V.

    2011-05-01

    In recent years, rapid increase has been observed in the population of microbes that are resistant to conventionally used antibiotics. Antifungal drug therapy is no exception and now resistance to many of the antifungal agents in use has emerged. Therefore, there is an inevitable and urgent medical need for antibiotics with novel antimicrobial mechanisms. Aspergillus glaucus is the potential cause of fatal brain infections and hypersensitivity pneumonitis in immunocompromised patients and leads to death despite aggressive multidrug antifungal therapy. In the present article, we describe the antifungal activity of multifunctional core-shell Fe 3O 4-Ag nanocolloids against A. glaucus isolates. Controlled experiments are also carried out with Ag nanocolloids in order to understand the role of core (Fe 3O 4) in the antifungal action. The minimum inhibitory concentration (MIC) of nanocolloids is determined by the micro-dilution method. MIC of A. glaucus is 2000 μg/mL. The result is quite promising and requires further investigations in order to develop a treatment methodology against this death causing fungus in immunocompromised patients.

  4. Structural and Functional Elucidation of Yeast Lanosterol 14α-Demethylase in Complex with Agrochemical Antifungals.

    PubMed

    Tyndall, Joel D A; Sabherwal, Manya; Sagatova, Alia A; Keniya, Mikhail V; Negroni, Jacopo; Wilson, Rajni K; Woods, Matthew A; Tietjen, Klaus; Monk, Brian C

    2016-01-01

    Azole antifungals, known as demethylase inhibitors (DMIs), target sterol 14α-demethylase (CYP51) in the ergosterol biosynthetic pathway of fungal pathogens of both plants and humans. DMIs remain the treatment of choice in crop protection against a wide range of fungal phytopathogens that have the potential to reduce crop yields and threaten food security. We used a yeast membrane protein expression system to overexpress recombinant hexahistidine-tagged S. cerevisiae lanosterol 14α-demethylase and the Y140F or Y140H mutants of this enzyme as surrogates in order characterize interactions with DMIs. The whole-cell antifungal activity (MIC50 values) of both the R- and S-enantiomers of tebuconazole, prothioconazole (PTZ), prothioconazole-desthio, and oxo-prothioconazole (oxo-PTZ) as well as for fluquinconazole, prochloraz and a racemic mixture of difenoconazole were determined. In vitro binding studies with the affinity purified enzyme were used to show tight type II binding to the yeast enzyme for all compounds tested except PTZ and oxo-PTZ. High resolution X-ray crystal structures of ScErg11p6×His in complex with seven DMIs, including four enantiomers, reveal triazole-mediated coordination of all compounds and the specific orientation of compounds within the relatively hydrophobic binding site. Comparison with CYP51 structures from fungal pathogens including Candida albicans, Candida glabrata and Aspergillus fumigatus provides strong evidence for a highly conserved CYP51 structure including the drug binding site. The structures obtained using S. cerevisiae lanosterol 14α-demethylase in complex with these agrochemicals provide the basis for understanding the impact of mutations on azole susceptibility and a platform for the structure-directed design of the next-generation of DMIs.

  5. Structural and Functional Elucidation of Yeast Lanosterol 14α-Demethylase in Complex with Agrochemical Antifungals

    PubMed Central

    Sagatova, Alia A.; Keniya, Mikhail V.; Negroni, Jacopo; Wilson, Rajni K.; Woods, Matthew A.; Monk, Brian C.

    2016-01-01

    Azole antifungals, known as demethylase inhibitors (DMIs), target sterol 14α-demethylase (CYP51) in the ergosterol biosynthetic pathway of fungal pathogens of both plants and humans. DMIs remain the treatment of choice in crop protection against a wide range of fungal phytopathogens that have the potential to reduce crop yields and threaten food security. We used a yeast membrane protein expression system to overexpress recombinant hexahistidine-tagged S. cerevisiae lanosterol 14α-demethylase and the Y140F or Y140H mutants of this enzyme as surrogates in order characterize interactions with DMIs. The whole-cell antifungal activity (MIC50 values) of both the R- and S-enantiomers of tebuconazole, prothioconazole (PTZ), prothioconazole-desthio, and oxo-prothioconazole (oxo-PTZ) as well as for fluquinconazole, prochloraz and a racemic mixture of difenoconazole were determined. In vitro binding studies with the affinity purified enzyme were used to show tight type II binding to the yeast enzyme for all compounds tested except PTZ and oxo-PTZ. High resolution X-ray crystal structures of ScErg11p6×His in complex with seven DMIs, including four enantiomers, reveal triazole-mediated coordination of all compounds and the specific orientation of compounds within the relatively hydrophobic binding site. Comparison with CYP51 structures from fungal pathogens including Candida albicans, Candida glabrata and Aspergillus fumigatus provides strong evidence for a highly conserved CYP51 structure including the drug binding site. The structures obtained using S. cerevisiae lanosterol 14α-demethylase in complex with these agrochemicals provide the basis for understanding the impact of mutations on azole susceptibility and a platform for the structure-directed design of the next-generation of DMIs. PMID:27907120

  6. Antifungal prophylaxis with posaconazole vs. fluconazole or itraconazole in pediatric patients with neutropenia.

    PubMed

    Döring, M; Eikemeier, M; Cabanillas Stanchi, K M; Hartmann, U; Ebinger, M; Schwarze, C-P; Schulz, A; Handgretinger, R; Müller, I

    2015-06-01

    Pediatric patients with hemato-oncological malignancies and neutropenia resulting from chemotherapy have a high risk of acquiring invasive fungal infections. Oral antifungal prophylaxis with azoles, such as fluconazole or itraconazole, is preferentially used in pediatric patients after chemotherapy. During this retrospective analysis, posaconazole was administered based on favorable results from studies in adult patients with neutropenia and after allogeneic hematopoietic stem cell transplantation. Retrospectively, safety, feasibility, and initial data on the efficacy of posaconazole were compared to fluconazole and itraconazole in pediatric and adolescent patients during neutropenia. Ninety-three pediatric patients with hemato-oncological malignancies with a median age of 12 years (range 9 months to 17.7 years) that had prolonged neutropenia (>5 days) after chemotherapy or due to their underlying disease, and who received fluconazole, itraconazole, or posaconazole as antifungal prophylaxis, were analyzed in this retrospective single-center survey. The incidence of invasive fungal infections in pediatric patients was low under each of the azoles. One case of proven aspergillosis occurred in each group. In addition, there were a few cases of possible invasive fungal infection under fluconazole (n = 1) and itraconazole (n = 2). However, no such cases were observed under posaconazole. The rates of potentially clinical drug-related adverse events were higher in the fluconazole (n = 4) and itraconazole (n = 5) groups compared to patients receiving posaconazole (n = 3). Posaconazole, fluconazole, and itraconazole are comparably effective in preventing invasive fungal infections in pediatric patients. Defining dose recommendations in these patients requires larger studies.

  7. Metal-Based Antibacterial and Antifungal Agents: Synthesis, Characterization, and In Vitro Biological Evaluation of Co(II), Cu(II), Ni(II), and Zn(II) Complexes With Amino Acid-Derived Compounds

    PubMed Central

    Chohan, Zahid H.; Arif, M.; Akhtar, Muhammad A.; Supuran, Claudiu T.

    2006-01-01

    A series of antibacterial and antifungal amino acid-derived compounds and their cobalt(II), copper(II), nickel(II), and zinc(II) metal complexes have been synthesized and characterized by their elemental analyses, molar conductances, magnetic moments, and IR, and electronic spectral measurements. Ligands (L1)−(L5) were derived by condensation of β-diketones with glycine, phenylalanine, valine, and histidine and act as bidentate towards metal ions (cobalt, copper, nickel, and zinc) via the azomethine-N and deprotonated-O of the respective amino acid. The stoichiometric reaction between the metal(II) ion and synthesized ligands in molar ratio of M : L (1 : 1) resulted in the formation of the metal complexes of type [M(L)(H2O)4]Cl (where M = Co(II), Cu(II), and Zn(II)) and of M : L (1 : 2) of type [M(L)2(H2O)2] (where M = Co(II), Cu(II), Ni(II), and Zn(II)). The magnetic moment data suggested for the complexes to have an octahedral geometry around the central metal atom. The electronic spectral data also supported the same octahedral geometry of the complexes. Elemental analyses and NMR spectral data of the ligands and their metal(II) complexes agree with their proposed structures. The synthesized ligands, along with their metal(II) complexes, were screened for their in vitro antibacterial activity against four Gram-negative (Escherichia coli, Shigella flexeneri, Pseudomonas aeruginosa, and Salmonella typhi) and two Gram-positive (Bacillus subtilis and Staphylococcus aureus) bacterial strains and for in vitro antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani, and Candida glaberata. The results of these studies show the metal(II) complexes to be more antibacterial/antifungal against one or more species as compared to the uncomplexed ligands. The brine shrimp bioassay was also carried out to study their in vitro cytotoxic properties. Five compounds, (3), (7), (10), (11), and (22), displayed

  8. Mechanisms of resistance to an azole fungicide in the grapevine powdery mildew fungus, Erysiphe necator

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We studied the mechanisms of azole resistance in the grapevine powdery mildew fungus, Erysiphe necator, by quantifying the sensitivity to myclobutanil (EC50) in 65 isolates from the eastern U.S. and 12 from Chile. From each isolate, we sequenced the gene for sterol 14a-demethylase (CYP51), and measu...

  9. Dimeric fluorescent energy transfer dyes comprising asymmetric cyanine azole-indolenine chromophores

    DOEpatents

    Glazer, Alexander N.; Benson, Scott C.

    1996-01-01

    Novel fluorescent DNA-staining dyes are provided combining asymmetric cyanine azole-indolenine dyes, which provide for strong DNA affinity, large Stokes shifts and emission in the red region of the spectrum. The dyes find particular application in gel electrophoresis and for labels which may be bound to a variety of compositions in a variety of contexts.

  10. Synthesis of new oxadiazole, pyrazole and pyrazolin-5-one bearing 2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)acetohydrazide analogs as potential antibacterial and antifungal agents.

    PubMed

    Mahesh, M; Bheemaraju, G; Manjunath, G; Venkata Ramana, P

    2016-01-01

    Two series of diversely substituted phenyldiazenyl(2-(4-methyl-2-oxo-2H-chromen-7-yloxy)acetyl)3,5-dimethyl-1H-pyrazole 11a-g and phenyldiazenyl-1-(2-(4-methyl-2-oxo-4-chromen-7-yloxy)acetyl)-3-methyl-1H-pyrazol-5(4)H-one 12a-j were synthesized. All these compounds were characterized by IR, NMR, mass spectra and elemental analyses. The compounds were evaluated for their in vitro antibacterial activity against some Gram-positive bacteria, Staphylococcus aureus, Bacillus subtilis, Gram-negative bacteria, Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi and screened for antifungal activity against A. niger, U. maydis. The compounds showed moderate to very good antibacterial activities.

  11. Comparison of the Sensititre YeastOne® dilution method with the Clinical Laboratory Standards Institute (CLSI) M27-A3 microbroth dilution reference method for determining MIC of eight antifungal agents on 102 yeast strains.

    PubMed

    Bertout, S; Dunyach, C; Drakulovski, P; Reynes, J; Mallié, M

    2011-02-01

    The Clinical Laboratory Standards Institute ([CLSI] formerly NCCLS) reference broth microdilution testing method (protocol M27-A3) was compared with a commercially available methods (Sensititre YeastOne(®)) by testing two quality control strains and 102 isolates of Candida sp. and Cryptococcus sp. against fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole, flucytosin, amphotericin B and caspofungin. Minimal inhibitory concentrations (MIC) endpoints were determined after 24h of incubation for Sensititre YeastOne(®) and after 24 and 48 h for CLSI microdilution method. Essential agreements between methods vary from 70.6 to 92.2%. Categorical agreements vary from 94.1% for 5FC to 72.6% for AMB. Sensititre YeastOne(®) reading appears to be useful for avoiding very major errors and this confirms the interest of this method for evaluating new antifungals activity in vitro.

  12. In Vitro and In Vivo Activity of a Novel Antifungal Small Molecule against Candida Infections

    PubMed Central

    Yuen, Kwok Yong; Wang, Yu; Yang, Dan; Samaranayake, Lakshman Perera

    2014-01-01

    Candida is the most common fungal pathogen of humans worldwide and has become a major clinical problem because of the growing number of immunocompromised patients, who are susceptible to infection. Moreover, the number of available antifungals is limited, and antifungal-resistant Candida strains are emerging. New and effective antifungals are therefore urgently needed. Here, we discovered a small molecule with activity against Candida spp. both in vitro and in vivo. We screened a library of 50,240 small molecules for inhibitors of yeast-to-hypha transition, a major virulence attribute of Candida albicans. This screening identified 20 active compounds. Further examination of the in vitro antifungal and anti-biofilm properties of these compounds, using a range of Candida spp., led to the discovery of SM21, a highly potent antifungal molecule (minimum inhibitory concentration (MIC) 0.2 – 1.6 µg/ml). In vitro, SM21 was toxic to fungi but not to various human cell lines or bacterial species and was active against Candida isolates that are resistant to existing antifungal agents. Moreover, SM21 was relatively more effective against biofilms of Candida spp. than the current antifungal agents. In vivo, SM21 prevented the death of mice in a systemic candidiasis model and was also more effective than the common antifungal nystatin at reducing the extent of tongue lesions in a mouse model of oral candidiasis. Propidium iodide uptake assay showed that SM21 affected the integrity of the cell membrane. Taken together, our results indicate that SM21 has the potential to be developed as a novel antifungal agent for clinical use. PMID:24465737

  13. Antifungal activity of steroidal glycosides from Yucca gloriosa L.

    PubMed

    Favel, A; Kemertelidze, E; Benidze, M; Fallague, K; Regli, P

    2005-02-01

    The antifungal activity of a crude steroidal glycoside extract from Yucca gloriosa flowers, named alexin, was investigated in vitro against a panel of human pathogenic fungi, yeasts as well as dermatophytes and filamentous species. The minimal inhibitory concentration (MIC) was determined by an agar dilution method. Alexin had a broad spectrum of antifungal activity, found to reside entirely in the spirostanoid fraction. The major tigogenyl glycosides, yuccaloeside B and yuccaloeside C, exhibited MICs between 0.39 and 6.25 microg[sol ]mL for all the tested yeast strains except for two (C. lusitaniae and C. kefyr). They were also active against several clinical Candida isolates known to be resistant to the usual antifungal agents. The MICs for the dermatophytes were between 0.78 and 12.5 microg[sol ]mL. The most sensitive filamentous species was A. fumigatus (MIC = 1.56 microg[sol ]mL). For most of the strains, the MICs of both glycosides were similar to those of the reference antifungal agent.

  14. In vitro antifungal susceptibility of Scopulariopsis brevicaulis isolates.

    PubMed

    Skóra, Magdalena; Macura, Anna B; Bulanda, Małgorzata

    2014-10-01

    In humans, Scopulariopsis is mainly associated with onychomycoses, rarely with cutaneous infections or with invasive mycoses. However, during the last two decades, deep infections caused by members of this genus have been increasing. Scopulariopsis brevicaulis is the most common species described as an etiologic agent of human disease. Previous antifungal susceptibility studies indicate that this species is resistant in vitro to the broad-spectrum antifungal agents that are available today. Here, we describe the antifungal activity of amphotericin B, terbinafine, ciclopirox, itraconazole, ketoconazole, and voriconazole against 40 S. brevicaulis isolates. Antifungal susceptibility tests were performed using a modified Clinical and Laboratory Standards Institute M38-A2 procedure. The results showed that itraconazole had the highest minimal inhibitory concentration (MIC) of >16 mg/l; amphotericin B, voriconazole, and ketoconazole MICs were ranging from 4 to >16 mg/l, 8 to >16 mg/l, and 8 to >16 mg/l, respectively; and the best activity was found with terbinafine and ciclopirox with MICs ranging from 0.5 to 16 mg/l and 1 to 8 mg/l, respectively.

  15. Clinical pharmacology of antifungal compounds.

    PubMed

    Groll, Andreas H; Gea-Banacloche, Juan C; Glasmacher, Axel; Just-Nuebling, Gudrun; Maschmeyer, Georg; Walsh, Thomas J

    2003-03-01

    Prompted by the worldwide surge in fungal infections, the past decade has witnessed a considerable expansion in antifungal drug research. New compounds have entered the clinical arena, and major progress has been made in defining paradigms of antifungal therapies. This article provides an up-to-date review on the clinical pharmacology, indications, and dosage recommendations of approved and currently investigational therapeutics for treatment of invasive fungal infections in adult and pediatric patients.

  16. Synthesis, Characterization and Antifungal Evaluation of Novel Thiochromanone Derivatives Containing Indole Skeleton.

    PubMed

    Han, Xiao-Yan; Zhong, Yi-Fan; Li, Sheng-Bin; Liang, Guo-Chao; Zhou, Guan; Wang, Xiao-Ke; Chen, Bao-Hua; Song, Ya-Li

    2016-09-01

    Invasive fungal disease constitutes a growing health problem and development of novel antifungal drugs with high potency and selectivity against new fungal molecular targets are urgently needed. In order to develop potent antifungal agents, a novel series of 6-alkyl-indolo[3,2-c]-2H-thiochroman derivatives were synthesized. Microdilution broth method was used to investigate antifungal activity of these compounds. Most of them showed good antifungal activity in vitro. Compound 4o showed the best antifungal activity, which (inhibition of Candida albicans and Cryptococcus neoformans) can be achieved at the concentration of 4 µg/mL. Compounds 4b (inhibition of Cryptococcus neoformans), 4j (inhibition of Cryptococcus neoformans), 4d (inhibition of Candida albicans) and 4h (inhibition of Candida albicans) also showed the best antifungal activity at the concentrations of 4 µg/mL. The molecular interactions between 4o and the N-myristoyltransferase of Candida albicans (PDB ID: 1IYL) were finally investigated through molecular docking. The results indicated that these thiochromanone derivatives containing indole skeleton could serve as promising leads for further optimization as novel antifungal agents.

  17. Antifungal susceptibility and virulence factors of clinically isolated dermatophytes in Tehran, Iran

    PubMed Central

    Afshari, Mohammad Ali; Shams-Ghahfarokhi, Masoomeh; Razzaghi-Abyaneh, Mehdi

    2016-01-01

    Background and Objectives: Dermatophytes possess a wide array of virulence factors and various antifungal susceptibility patterns which influence their pathogenesis in humans and animals. The aim of this study was to evaluate antifungal susceptibility and keratinase and proteinase activity of 49 dermatophyte strains from the genera Microsporum, Trichophyton and Epidermophyton which were isolated from human cases of dermatophytosis. Materials and Methods: Forty-nine dermatophyte strains isolated from clinical samples were cultured on general and specific culture media. Keratinase and proteinase activity was screened on solid mineral media and confirmed in liquid cultures. Drug susceptibility toward azoles (fluconazole, ketoconazole and itraconazole), griseofulvin and terbinafine was evaluated using disk diffusion method on Mueller-Hinton agar and minimum inhibitory concentrations (MICs) were determined using microbroth dilution assay according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Results: Our results indicated that clinically isolated dermatophytes from 7 major species produced keratinase and proteinase at different extents. The mean keratinase and proteinase activity was reported as 6.69 ± 0.31 (U/ml) and 2.10 ± 0.22 (U/ml) respectively. Disk diffusion and microbroth dilution (MIC) results of antifungal susceptibility testing showed that ketoconazole was the most effective drug against Epidermophyton floccosum and Trichophyton mentagrophytes, itraconazole against T. rubrum and E. floccosum, and griseofulvin and terbinafine against Trichophyton verrucosum. Our results showed that all dermatophyte isolates were resistant to fluconazole. Overall, ketoconazole and itraconazole were the most effective drugs for all dermatophyte species tested. Conclusion: Our results showed that antifungal susceptibility testing is an urgent need to select drugs of choice for treatment of different types of dermatophytosis and further indicated the

  18. Systemic mycoses in the immunocompromised host: an update in antifungal therapy.

    PubMed

    Kontoyiannis, D P; Mantadakis, E; Samonis, G

    2003-04-01

    Despite significant advances in the management of immunosuppressed patients, invasive fungal infections remain an important life-threatening complication. In the last decade several new antifungal agents, including compounds in pre-existing classes (new generation of triazoles, polyenes in lipid formulations) and novel classes of antifungals with a unique mechanism of action (echinocandins), have been introduced in clinical practice. Ongoing and future studies will determine their exact role in the management of different mycoses. The acceleration of antifungal drug discovery offers promise for the management of these difficult to treat opportunistic infections.

  19. Enhancement of the Antifungal Activity of Antimicrobial Drugs by Eugenia uniflora L.

    PubMed Central

    Santos, Karla K.A.; Matias, Edinardo F.F.; Tintino, Saulo R.; Souza, Celestina E.S.; Braga, Maria F.B.M.; Guedes, Gláucia M.M.; Costa, José G.M.; Menezes, Irwin R.A.

    2013-01-01

    Abstract Candidiasis is the most frequent infection by opportunistic fungi such as Candida albicans, Candida tropicalis, and Candida krusei. Ethanol extract from Eugenia uniflora was assayed, for its antifungal activity, either alone or combined with four selected chemotherapeutic antimicrobial agents, including anphotericin B, mebendazole, nistatin, and metronidazole against these strains. The obtained results indicated that the association of the extract of E. uniflora to metronidazole showed a potential antifungal activity against C. tropicalis. However, no synergistic activity against the other strains was observed, as observed when the extract was associated with the other, not enhancing their antifungal activity. PMID:23819641

  20. The Rho1 GTPase-activating Protein CgBem2 Is Required for Survival of Azole Stress in Candida glabrata*

    PubMed Central

    Borah, Sapan; Shivarathri, Raju; Kaur, Rupinder

    2011-01-01

    Invasive fungal infections are common clinical complications of neonates, critically ill, and immunocompromised patients worldwide. Candida species are the leading cause of disseminated fungal infections, with Candida albicans being the most prevalent species. Candida glabrata, the second/third most common cause of candidemia, shows reduced susceptibility to a widely used antifungal drug fluconazole. Here, we present findings from a screen of 9134 C. glabrata Tn7 insertion mutants for altered survival profiles in the presence of fluconazole. We have identified two components of RNA polymerase II mediator complex, three players of Rho GTPase-mediated signaling cascade, and two proteins implicated in actin cytoskeleton biogenesis and ergosterol biosynthesis that are required to sustain viability during fluconazole stress. We show that exposure to fluconazole leads to activation of the protein kinase C (PKC)-mediated cell wall integrity pathway in C. glabrata. Our data demonstrate that disruption of a RhoGAP (GTPase activating protein) domain-containing protein, CgBem2, results in bud-emergence defects, azole susceptibility, and constitutive activation of CgRho1-regulated CgPkc1 signaling cascade and cell wall-related phenotypes. The viability loss of Cgbem2Δ mutant upon fluconazole treatment could be partially rescued by the PKC inhibitor staurosporine. Additionally, we present evidence that CgBEM2 is required for the transcriptional activation of genes encoding multidrug efflux pumps in response to fluconazole exposure. Last, we report that Hsp90 inhibitor geldanamycin renders fluconazole a fungicidal drug in C. glabrata. PMID:21832071

  1. Sensitisation of an Azole-Resistant Aspergillus fumigatus Strain containing the Cyp51A-Related Mutation by Deleting the SrbA Gene

    PubMed Central

    Hagiwara, Daisuke; Watanabe, Akira; Kamei, Katsuhiko

    2016-01-01

    Azoles are widely used for controlling fungal growth in both agricultural and medical settings. The target protein of azoles is CYP51, a lanosterol 14-α-demethylase involved in the biosynthesis of ergosterol. Recently, a novel azole resistance mechanism has arisen in pathogenic fungal species Aspergillus fumigatus. Resistant strains contain a 34-bp or 46-bp tandem repeat (TR) in the promoter of cyp51A, and have disseminated globally in a short period of time. In this study, we investigated whether an azole-resistant strain with a 46-bp TR (TR46/Y121F/T289A) could be sensitised to azoles by deletion of srbA, encoding a direct regulator of cyp51A. The loss of SrbA did not affect colony growth or conidia production, but decreased expression of cyp51A. The srbA deletion strain showed hyper-susceptibility to medical azoles as well as azole fungicides, while its sensitivity to non-azole fungicides was unchanged. This is the first demonstration that deletion of a regulator of cyp51A can sensitise an azole-resistant A. fumigatus strain. This finding may assist in the development of new drugs to help combat life-threatening azole-resistant fungal pathogens. PMID:27934927

  2. Mechanisms of echinocandin antifungal drug resistance

    PubMed Central

    Perlin, David S.

    2015-01-01

    Fungal infections due to Candida and Aspergillus species cause extensive morbidity and mortality, especially among immunosuppressed patients, and antifungal therapy is critical to patient management. Yet only a few drug classes are available to treat invasive fungal diseases, and this problem is compounded by the emergence of antifungal resistance. Echinocandin drugs are the preferred choice to treat candidiasis. They are the first cell wall–active agents and target the fungal-specific enzyme glucan synthase, which catalyzes the biosynthesis of β-1,3-glucan, a key cell wall polymer. Therapeutic failures occur rarely among common Candida species, with the exception of Candida glabrata, which are frequently multidrug resistant. Echinocandin resistance in susceptible species is always acquired during therapy. The mechanism of resistance involves amino acid changes in hot-spot regions of Fks subunits of glucan synthase, which decrease the sensitivity of the enzyme to drug. Cellular stress response pathways lead to drug adaptation, which promote the formation of resistant fks strains. Clinical factors promoting echinocandin resistance include empiric therapy, prophylaxis, gastrointestinal reservoirs, and intra-abdominal infections. A better understanding of the echinocandin resistance mechanism, along with cellular and clinical factors promoting resistance, will promote more effective strategies to overcome and prevent echinocandin resistance. PMID:26190298

  3. Augmenting the efficacy of antifungal intervention via chemo-biological approaches

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mycotic infection is becoming a serious health problem since effective antifungal agents for control of pathogenic fungi, especially drug-resistant pathogens, is often very limited. Fungal resistance to antimycotic agents frequently involves mutations caused by environmental stressors. In fungal pat...

  4. In Vitro Antifungal Activity of Sertraline and Synergistic Effects in Combination with Antifungal Drugs against Planktonic Forms and Biofilms of Clinical Trichosporon asahii Isolates

    PubMed Central

    Cong, Lin; Liao, Yong; Yang, Suteng

    2016-01-01

    Trichosporon asahii (T. asahii) is the major pathogen of invasive trichosporonosis which occurred mostly in immunocompromised patients. The biofilms formation ability of T. asahii may account for resistance to antifungal drugs and results a high mortality rate. Sertraline, a commonly prescribed antidepressant, has been demonstrated to show in vitro and in vivo antifungal activities against many kinds of pathogenic fungi, especially Cryptococcus species. In the present study, the in vitro activities of sertraline alone or combined with fluconazole, voriconazole, itraconazole, caspofungin and amphotericin B against planktonic forms and biofilms of 21 clinical T. asahii isolates were evaluated using broth microdilution checkerboard method and XTT reduction assay, respectively. The fractional inhibitory concentration index (FICI) was used to interpret drug interactions. Sertraline alone exhibited antifungal activities against both T. asahii planktonic cells (MICs, 4–8 μg/ml) and T. asahii biofilms (SMICs, 16–32 μg/ml). Furthermore, SRT exhibited synergistic effects against T. asahii planktonic cells in combination with amphotericin B, caspofungin or fluconazole (FICI≤0.5) and exhibited synergistic effects against T. asahii biofilms in combination with amphotericin B (FICI≤0.5). SRT exhibited mostly indifferent interactions against T. asahii biofilms in combination with three azoles in this study. Sertraline-amphotericin B combination showed the highest percentage of synergistic effects against both T. asahii planktonic cells (90.5%) and T. asahii biofilms (81.0%). No antagonistic interaction was observed. Our study suggests the therapeutic potential of sertraline against invasive T. asahii infection, especially catheter-related T. asahii infection. Further in vivo studies are needed to validate our findings. PMID:27930704

  5. Comparing Azole Plasma Trough Levels in Lung Transplant Recipients: Percentage of Therapeutic Levels and Intrapatient Variability

    PubMed Central

    Weber, Alexandra; Ihle, Franziska; Matthes, Sandhya; Ceelen, Felix; Zimmermann, Gregor; Kneidinger, Nikolaus; Schramm, Rene; Winter, Hauke; Zoller, Michael; Vogeser, Michael; Behr, Juergen; Neurohr, Claus

    2017-01-01

    Background: This study compared therapeutic azole plasma trough levels (APL) of the azole antimycotics itraconazole (ITR), voriconazole (VOR), and posaconazole (POS) in lung transplant recipients and analyzed the influencing factors. In addition, intrapatient variability for each azole was determined. Methods: From July 2012 to July 2015, 806 APL of ITR, VOR, posaconazole liquid (POS-Liq), and posaconazole tablets (POS-Tab) were measured in 173 patients of the Munich Lung Transplantation Program. Therapeutic APL were defined as follows: ITR, ≥700 ng/mL; VOR, 1000–5500 ng/mL; and POS, ≥700 ng/mL (prophylaxis) and ≥1000 ng/mL (therapy). Results: VOR and POS-Tab reached the highest number of therapeutic APL, whereas POS-Liq showed the lowest percentage (therapy: ITR 50%, VOR 70%, POS-Liq 38%, and POS-Tab 82%; prophylaxis: ITR 62%, VOR 85%, POS-Liq 49%, and POS-Tab 76%). Risk factors for subtherapeutic APL of all azoles were the azole dose (ITR, P < 0.001; VOR, P = 0.002; POS-Liq, P = 0.006) and age over 60 years (ITR, P = 0.003; VOR, P = 0.002; POS-Liq, P = 0.039; POS-Tab, P < 0.001). Cystic fibrosis was a significant risk factor for subtherapeutic APL for VOR and POS-Tab (VOR, P = 0.002; POS-Tab, P = 0.005). Double lung transplantation (LTx) was significantly associated with less therapeutic APL for VOR and POS-Liq (VOR, P = 0.030; POS-Liq, P < 0.001). Concomitant therapy with 80 mg pantoprazole led to significantly fewer therapeutic POS APL as compared to 40 mg (POS-Liq, P = 0.015; POS-Tab, P < 0.001). VOR displayed the greatest intrapatient variability (46%), whereas POS-Tab showed the lowest (32%). Conclusions: Our study showed that VOR and POS-Tab achieve the highest percentage of therapeutic APL in patients with LTx; POS-Tab showed the lowest intrapatient variability. APL are significantly influenced by azole dose, age, cystic fibrosis, type of LTx, and comedication with proton-pump inhibitors. Considering the high number of subtherapeutic APL

  6. Prescribing Pattern of Antifungal Medications at a Tertiary Care Hospital in Oman

    PubMed Central

    Alzaabi, Mohammed A.; Alghafri, Fatma

    2016-01-01

    Introduction Inappropriate use of antifungal agents is implicated in the global burden of antifungal resistance, adverse outcomes like persistent infections, unnecessary exposure and increased cost. Data collection from time to time is to be done in order to have a check on the resistance/sensitivity pattern of the commonly prescribed antifungal drugs. Aim To describe the pattern of antifungal drug prescription and administration to patients attending a university hospital in Oman. Materials and Methods This was a descriptive, retrospective cross-sectional study conducted at Sultan Qaboos University Hospital (SQUH), a university hospital in Oman that covered the electronic patient’s data for a period of one year (January 2013 to December 2013). The study included inpatients and outpatients of all ages and both genders attending SQUH and receiving antifungal medications at the study period. Frequencies and percentages were reported for categorical variables, while the mean and standard deviation were used to summarize the data for continuous variables. Results A total of 1353 antifungal drug prescriptions were prescribed for 244 patients. More than half of all antifungal drug prescriptions were prescribed by haematology, infectious disease and family medicine departments. The majority of patients to whom these drugs were prescribed were diagnosed to have infectious diseases followed by prophylactic use in leukaemias and immunocompromised conditions. Fluconazole was the most commonly prescribed antifungal drug (n=715, 52.8%) followed by nystatin and voriconazole (n=233; 17.2% and n=152; 11.2%, respectively). Conclusion This study will help in understanding antifungal prescription practices and help in directing future studies and also in developing local policies for appropriate use of antifungal drugs. PMID:28208876

  7. Saccharomyces cerevisiae vaginitis: microbiology and in vitro antifungal susceptibility.

    PubMed

    Echeverría-Irigoyen, María Julia; Eraso, Elena; Cano, Josep; Gomáriz, María; Guarro, Josep; Quindós, Guillermo

    2011-09-01

    Genitourinary infections by Saccharomyces cerevisiae are rare. Here, we describe eight S. cerevisiae vulvovaginitis episodes where molecular (Affirm VPIII) and conventional microbiological methods (culture and carbohydrate assimilation) have proven to be inadequate for diagnostic purposes. DNA sequencing allowed the correct identification of the pathogen. All isolates were susceptible to most antifungal agents, with two of them also found to be susceptible-dose-dependent to itraconazole.

  8. Current evidence of antifungal prophylaxis and therapy in pediatric patients

    PubMed Central

    Giacchino, Mareva; Milano, Giuseppe Maria; Carraro, Francesca; Bezzio, Stefania; Pegoraro, Anna; Aversa, Franco; Cesaro, Simone

    2011-01-01

    Invasive fungal infections (IFI) are an important complication in pediatric haematological and oncological patients who undergo intensive chemotherapy for leukemia, solid tumour at advanced stage or relapsed, and hematopoietic stem cell transplantation. The incidence of IFI is lower than bacterial infection but mortality rate remains high. This review is designed to help paediatric oncologists in choosing the appropriate anti-fungal strategy and agents for prophylaxis, empirical, pre-emptive and specific therapy on the basis of published evidence. PMID:21647279

  9. Current evidence of antifungal prophylaxis and therapy in pediatric patients.

    PubMed

    Giacchino, Mareva; Milano, Giuseppe Maria; Carraro, Francesca; Bezzio, Stefania; Pegoraro, Anna; Aversa, Franco; Cesaro, Simone

    2011-02-24

    Invasive fungal infections (IFI) are an important complication in pediatric haematological and oncological patients who undergo intensive chemotherapy for leukemia, solid tumour at advanced stage or relapsed, and hematopoietic stem cell transplantation. The incidence of IFI is lower than bacterial infection but mortality rate remains high. This review is designed to help paediatric oncologists in choosing the appropriate anti-fungal strategy and agents for prophylaxis, empirical, pre-emptive and specific therapy on the basis of published evidence.

  10. Stepwise design, synthesis, and in vitro antifungal screening of (Z)-substituted-propenoic acid derivatives with potent broad-spectrum antifungal activity

    PubMed Central

    Khedr, Mohammed A

    2015-01-01

    Fungal infections are a main reason for the high mortality rate worldwide. It is a challenge to design selective antifungal agents with broad-spectrum activity. Lanosterol 14α-demethylase is an attractive target in the design of antifungal agents. Seven compounds were selected from a number of designed compounds using a rational docking study. These compounds were synthesized and evaluated for their antifungal activity. In silico study results showed the high binding affinity to lanosterol 14α-demethylase (−24.49 and −25.83 kcal/mol) for compounds V and VII, respectively; these values were greater than those for miconazole (−18.19 kcal/mol) and fluconazole (−16.08 kcal/mol). Compound V emerged as the most potent antifungal agent among all compounds with a half maximal inhibitory concentration of 7.01, 7.59, 7.25, 31.6, and 41.6 µg/mL against Candida albicans, Candida parapsilosis, Aspergillus niger, Trichophyton rubrum, and Trichophyton mentagrophytes, respectively. The antifungal activity for most of the synthesized compounds was more potent than that of miconazole and fluconazole. PMID:26309398

  11. Geographic and temporal trends in isolation and antifungal susceptibility of Candida parapsilosis: a global assessment from the ARTEMIS DISK Antifungal Surveillance Program, 2001 to 2005.

    PubMed

    Pfaller, M A; Diekema, D J; Gibbs, D L; Newell, V A; Ng, K P; Colombo, A; Finquelievich, J; Barnes, R; Wadula, J

    2008-03-01

    We examined data from the ARTEMIS DISK Antifungal Surveillance Program to describe geographic and temporal trends in the isolation of Candida parapsilosis from clinical specimens and the in vitro susceptibilities of 9,371 isolates to fluconazole and voriconazole. We also report the in vitro susceptibility of bloodstream infection (BSI) isolates of C. parapsilosis to the echinocandins, anidulafungin, caspofungin, and micafungin. C. parapsilosis represented 6.6% of the 141,383 isolates of Candida collected from 2001 to 2005 and was most common among isolates from North America (14.3%) and Latin America (9.9%). High levels of susceptibility to both fluconazole (90.8 to 95.8%) and voriconazole (95.3 to 98.1%) were observed in all geographic regions with the exception of the Africa and Middle East region (79.3 and 85.8% susceptible to fluconazole and voriconazole, respectively). C. parapsilosis was most often isolated from blood and skin and/or soft tissue specimens and from patients hospitalized in the medical, surgical, intensive care unit (ICU) and dermatology services. Notably, isolates from the surgical ICU were the least susceptible to fluconazole (86.3%). There was no evidence of increasing azole resistance over time among C. parapsilosis isolates tested from 2001 to 2005. Of BSI isolates tested against the three echinocandins, 92, 99, and 100% were inhibited by concentrations of < or = 2 microg/ml of anidulafungin (621 isolates tested), caspofungin (1,447 isolates tested), and micafungin (539 isolates tested), respectively. C. parapsilosis is a ubiquitous pathogen that remains susceptible to the azoles and echinocandins; however, both the frequency of isolation and the resistance of C. parapsilosis to fluconazole and voriconazole may vary by geographic region and clinical service.

  12. Probiotics as Antifungals in Mucosal Candidiasis.

    PubMed

    Matsubara, Victor H; Bandara, H M H N; Mayer, Marcia P A; Samaranayake, Lakshman P

    2016-05-01

    Candidais an opportunistic pathogen that causes mucosal and deep systemic candidiasis. The emergence of drug resistance and the side effects of currently available antifungals have restricted their use as long-term prophylactic agents for candidal infections. Given this scenario, probiotics have been suggested as a useful alternative for the management of candidiasis. We analyzed the available data on the efficacy of probiotics in candidal colonization of host surfaces. A number of well-controlled studies indicate that probiotics, particularly lactobacilli, suppressCandidagrowth and biofilm development in vitro.A few clinical trials have also shown the beneficial effects of probiotics in reducing oral, vaginal, and enteric colonization byCandida; alleviation of clinical signs and symptoms; and, in some cases, reducing the incidence of invasive fungal infection in critically ill patients. Probiotics may serve in the future as a worthy ally in the battle against chronic mucosal candidal infections.

  13. Terbinafine: novel formulations that potentiate antifungal activities.

    PubMed

    Ma, Y; Chen, X; Guan, S

    2015-03-01

    Terbinafine, an orally and topically active antifungal agent, has been available for the treatment of dermatophytic infections and onychomycosis for more than a decade. In addition, oral administration has been shown to be associated with drug-drug interactions, hepatotoxicity, low concentration at the infected sites, gastrointestinal and systemic side effects and other adverse effects. Since topical drug delivery can provide higher patient compliance, allow immediate access to the infected site and reduce unwanted systemic drug exposure, an improved topical drug delivery approach with high permeability, sustained release and prolonged retainment could overcome the limitations and side effects caused by oral administration. Conventional topical formulations cannot keep the drug in the targeted sites for a long duration of time and hence a novel drug delivery that can avoid the side effects while still providing sustained efficacy in treatment should be developed. This brief review of novel formulations based on polymers and nanostructure carriers provides insight into the efficacy and topical delivery of terbinafine.

  14. Lack of hepato- and nephrotoxicity induced by antifungal drug voriconazole in laboratory rats.

    PubMed

    Somchit, Nhareet; Chung, Jun Hung; Yaacob, Azhar; Ahmad, Zuraini; Zakaria, Zainul A; Kadir, Arifah A

    2012-07-01

    Voriconazole is a new, potent broad-spectrum triazole systemic antifungal drug, a second-generation azole antifungal that is increasing in popularity, especially for the treatment of invasive aspergillosis and fluconazole-resistant invasive Candida infections. However, it is also known to induce hepatotoxicity clinically. The aim of this study was to investigate the hepatotoxicity and nephrotoxicity potential of voriconazole in vivo in rats. Forty rats were treated intraperitoneally with voriconazole as single (0, 10, l00, and 200 mg/kg) or repeated (0, 10, 50, and l00 mg/kg per day for 14 days) doses. Venous blood was collected for the repeated-dose group on days 1 and 14. Rats were sacrificed 24 hours after the last dose. Body weight, liver weight, and kidney weight of rats were recorded. Livers and kidneys samples were taken for histological and transmission electron microscopy (TEM) analysis. Results revealed that voriconazole had no effects on serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphotase, gamma glutamyl transpeptidase, blood urea nitrogen, and creatinine for both the single- and repeated-dose groups. However, histologically, in the repeated 50- and 100-mg/kg voriconazole-treated rats, mild focal inflammation was observed. Under TEM, only small changes in the 100 mg/kg/day group were revealed. These results collectively demonstrated that voriconazole did not induce significant hepatotoxicity and nephrotoxicity, even at very high doses.

  15. In vitro susceptibility of 137 Candida sp. isolates from HIV positive patients to several antifungal drugs.

    PubMed

    Magaldi, S; Mata, S; Hartung, C; Verde, G; Deibis, L; Roldán, Y; Marcano, C

    2001-01-01

    Oropharyngeal candidiasis caused by various species of Candida is one of the most common infections in HIV seropositive or AIDS patients. Drug resistance among these yeasts is an increasing problem. We studied the frequency of resistance profile to fluconazole, itraconazole, ketoconazole, amphotericin B and terbinafine of 137 isolates of Candida sp. From HIV positive or AIDS patients with oropharyngeal candidiasis at Instituto de Inmunología, U.C.V. and the Hospital "Jose Ignacio Baldó", Caracas Venezuela, using the well diffusion susceptibility test (Magaldi et al.). We found that nearly 10% of C. albicans isolates were primarily fluconazole resistant, 45% of C. albicans isolates from patients with previous treatment were resistant to fluconazole, of which 93% showed cross-resistance to itraconazole, and even about 30% of C. tropicalis (n = 13) were resistant to fluconazole and/or itraconazole. To this respect, several recent reports have been described antifungal cross-resistance among azoles. Therefore, we consider that C. tropicalis should be added to the growing list of yeast in which antifungal drug resistance is common. This report could be useful for therapeutic aspect in AIDS patients with oral candidiasis.

  16. First description of Candida nivariensis in Brazil: antifungal susceptibility profile and potential virulence attributes

    PubMed Central

    Figueiredo-Carvalho, Maria Helena Galdino; Ramos, Livia de Souza; Barbedo, Leonardo Silva; Chaves, Alessandra Leal da Silva; Muramoto, Ilda Akemi; dos Santos, André Luis Souza; Almeida-Paes, Rodrigo; Zancopé-Oliveira, Rosely Maria

    2016-01-01

    This study evaluated the antifungal susceptibility profile and the production of potential virulence attributes in a clinical strain of Candida nivariensis for the first time in Brazil, as identified by sequencing the internal transcribed spacer (ITS)1-5.8S-ITS2 region and D1/D2 domains of the 28S of the rDNA. For comparative purposes, tests were also performed with reference strains. All strains presented low planktonic minimal inhibitory concentrations (PMICs) to amphotericin B (AMB), caspofungin (CAS), and voriconazole. However, our strain showed elevated planktonic MICs to posaconazole (POS) and itraconazole, in addition to fluconazole resistance. Adherence to inert surfaces was conducted onto glass and polystyrene. The biofilm formation and antifungal susceptibility on biofilm-growing cells were evaluated by crystal violet staining and a XTT reduction assay. All fungal strains were able to bind both tested surfaces and form biofilm, with a binding preference to polystyrene (p < 0.001). AMB promoted significant reductions (≈50%) in biofilm production by our C. nivariensis strain using both methodologies. This reduction was also observed for CAS and POS, but only in the XTT assay. All strains were excellent protease producers and moderate phytase producers, but lipases were not detected. This study reinforces the pathogenic potential of C. nivariensis and its possible resistance profile to the azolic drugs generally used for candidiasis management. PMID:26814644

  17. Activation of Melanin Synthesis in Alternaria infectoria by Antifungal Drugs

    PubMed Central

    Fernandes, Chantal; Prados-Rosales, Rafael; Silva, Branca M. A.; Nakouzi-Naranjo, Antonio; Zuzarte, Mónica; Chatterjee, Subhasish; Stark, Ruth E.; Casadevall, Arturo

    2015-01-01

    The importance of Alternaria species fungi to human health ranges from their role as etiological agents of serious infections with poor prognoses in immunosuppressed individuals to their association with respiratory allergic diseases. The present work focuses on Alternaria infectoria, which was used as a model organism of the genus, and was designed to unravel melanin production in response to antifungals. After we characterized the pigment produced by A. infectoria, we studied the dynamics of 1,8-dihydroxynaphthalene (DHN)-melanin production during growth, the degree of melanization in response to antifungals, and how melanization affected susceptibility to several classes of therapeutic drugs. We demonstrate that A. infectoria increased melanin deposition in cell walls in response to nikkomycin Z, caspofungin, and itraconazole but not in response to fluconazole or amphotericin B. These results indicate that A. infectoria activates DHN-melanin synthesis in response to certain antifungal drugs, possibly as a protective mechanism against these drugs. Inhibition of DHN-melanin synthesis by pyroquilon resulted in a lower minimum effective concentration (MEC) of caspofungin and enhanced morphological changes (increased hyphal balloon size), characterized by thinner and less organized A. infectoria cell walls. In summary, A. infectoria synthesizes melanin in response to certain antifungal drugs, and its susceptibility is influenced by melanization, suggesting the therapeutic potential of drug combinations that affect melanin synthesis. PMID:26711773

  18. Activation of Melanin Synthesis in Alternaria infectoria by Antifungal Drugs.

    PubMed

    Fernandes, Chantal; Prados-Rosales, Rafael; Silva, Branca M A; Nakouzi-Naranjo, Antonio; Zuzarte, Mónica; Chatterjee, Subhasish; Stark, Ruth E; Casadevall, Arturo; Gonçalves, Teresa

    2015-12-28

    The importance of Alternaria species fungi to human health ranges from their role as etiological agents of serious infections with poor prognoses in immunosuppressed individuals to their association with respiratory allergic diseases. The present work focuses on Alternaria infectoria, which was used as a model organism of the genus, and was designed to unravel melanin production in response to antifungals. After we characterized the pigment produced by A. infectoria, we studied the dynamics of 1,8-dihydroxynaphthalene (DHN)-melanin production during growth, the degree of melanization in response to antifungals, and how melanization affected susceptibility to several classes of therapeutic drugs. We demonstrate that A. infectoria increased melanin deposition in cell walls in response to nikkomycin Z, caspofungin, and itraconazole but not in response to fluconazole or amphotericin B. These results indicate that A. infectoria activates DHN-melanin synthesis in response to certain antifungal drugs, possibly as a protective mechanism against these drugs. Inhibition of DHN-melanin synthesis by pyroquilon resulted in a lower minimum effective concentration (MEC) of caspofungin and enhanced morphological changes (increased hyphal balloon size), characterized by thinner and less organized A. infectoria cell walls. In summary, A. infectoria synthesizes melanin in response to certain antifungal drugs, and its susceptibility is influenced by melanization, suggesting the therapeutic potential of drug combinations that affect melanin synthesis.

  19. Human Pharmacogenomic Variations and Their Implications for Antifungal Efficacy

    PubMed Central

    Meletiadis, Joseph; Chanock, Stephen; Walsh, Thomas J.

    2006-01-01

    Pharmacogenomics is defined as the study of the impacts of heritable traits on pharmacology and toxicology. Candidate genes with potential pharmacogenomic importance include drug transporters involved in absorption and excretion, phase I enzymes (e.g., cytochrome P450-dependent mixed-function oxidases) and phase II enzymes (e.g., glucuronosyltransferases) contributing to metabolism, and those molecules (e.g., albumin, A1-acid glycoprotein, and lipoproteins) involved in the distribution of antifungal compounds. By using the tools of population genetics to define interindividual differences in drug absorption, distribution, metabolism, and excretion, pharmacogenomic models for genetic variations in antifungal pharmacokinetics can be derived. Pharmacogenomic factors may become especially important in the treatment of immunocompromised patients or those with persistent or refractory mycoses that cannot be explained by elevated MICs and where rational dosage optimization of the antifungal agent may be particularly critical. Pharmacogenomics has the potential to shift the paradigm of therapy and to improve the selection of antifungal compounds and adjustment of dosage based upon individual variations in drug absorption, metabolism, and excretion. PMID:17041143

  20. Recent advances in antifungal pharmacotherapy for invasive fungal infections.

    PubMed

    Gallagher, Jason C; MacDougall, Conan; Ashley, Elizabeth S Dodds; Perfect, John R

    2004-04-01

    Invasive fungal infections carry significant morbidity and mortality. Candida species have become one of the most frequent causes of bloodstream infections, and infections caused by molds such as Aspergillus are becoming more frequent in immunocompromised patients. As this population grows, more invasive fungal infections can be anticipated. In the past, treatment options have been limited for many of these infections due to toxicity and efficacy concerns with the available antifungals. Fortunately, the past few years have brought exciting developments in antifungal pharmacotherapy. Lipid-based formulations of amphotericin B were introduced in the 1990s to attenuate adverse effects caused by amphotericin B deoxycholate (Fungizone, Bristol-Myers Squibb). Most recently, the echinocandins have been added to our antifungal regimen with the introduction of caspofungin (Cancidas, Merck and Co.) and voriconazole (Vfend, Pfizer), a new triazole, has come to market. The introduction of the echinocandins has invigorated the discussion about combination ant