Treatment Of Fungal Diseases Research Articles

Design and synthesis of new potent inhibitors of farnesyl pyrophosphate synthase.

Predictive QSAR models for the inhibition activities of nitrogen-containing bisphosphonates (N-BPs) against farnesyl pyrophosphate synthase (FPPS) from Leishmania major (LeFPPS) were developed using a data set of 97 compounds. The QSAR models were developed through the use of Artificial Neural Networks and Random Forest learning procedures. The predictive ability of the models was tested by means of leave-one-out cross-validation; Q(2)values ranging from 0.45-0.79 were obtained for the regression models. The consensus prediction for the external evaluation set afforded high predictive power (Q(2)=0.76 for 35 compounds). The robustness of the QSAR models was also evaluated using a Y-randomization procedure. A small set of 6 new N-BPs were designed and synthesized applying the Michael reaction of tetrakis (trimethylsilyl) ethenylidene bisphosphonate with amines. The inhibition activities of these compounds against LeFPPS were predicted by the developed QSAR models and were found to correlate with their fungistatic activities against Candida albicans. The antifungal activities of N-BPs bearing n-butyl and cyclopropyl side chains exceeded the activities of Fluconazole, a triazole-containing antifungal drug. In conclusion, the N-BPs developed here present promising candidate drugs for the treatment of fungal diseases.

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Synthesis and structure of copper nanoparticles and their antiinfection properties

Copper nanoparticles localized on the surface of cotton fabric are synthesized. The structure and composition of the particles are determined by EXAFS, TEM, EPR, and XRF. The nanoparticles obtained are suggested to have a core shell structure. The study shows that copper is distributed in the fabric in the form of nanoparticles associated with fragments of macromolecules, on one hand, and in the form of nanoparticle conglomerates on the surfaces of the filaments of fibers, on the other hand. Modification of natural fabrics by copper nanoparticles results in complete destruction of Epidermophyton colonies and suppresses growth of Candida colonies, which makes it possible to apply such fabric in treatment of fungal diseases and in antiseptic treatment and healing of septic wounds.

Treatment of fungal disease in the setting of neutropenia

Invasive fungal infections are important causes of morbidity and attributable mortality in neutropenic patients with hematological malignancies, myelodysplasia, and aplastic anemia. Successful risk-based strategies can be implemented for prophylaxis, empirical therapy, and preemptive therapy for the prevention and early treatment of invasive fungal infections in neutropenic hosts. The use of echinocandins for invasive candidiasis and voriconazole for invasive aspergillosis has significantly improved outcome. Recent studies demonstrate, however, that resistant fungal pathogens may emerge during the course of these antifungal interventions. Although triazole-resistant Candida spp. have been well described as causes of breakthrough candidemia, other organisms now pose a similar threat. Such organisms include echinocandin-resistant Candida glabrata and Candida parapsilosis species complex. The Mucorales, Fusarium spp., and Scedosporium spp. may emerge in the setting of voriconazole prophylaxis. The challenges of these emerging pathogens underscore the need for the development of new antifungal agents and strategies.

Treatment of invasive fungal diseases in children

Treatment of invasive fungal diseases in children

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Isolation of the volatile fraction from Apium graveolens L. (Apiaceae) by supercritical carbon dioxide extraction and hydrodistillation: Chemical composition and antifungal activity

Apium graveolens L. (wild celery), belonging to the family of Apiaceae, is a scaposus hemicryptophyte. Instead, the cultivate plant is an annual or biennial herb widely used as a spice and seasoning in food. A broad range of biological activities have been attributed to A. graveolens. These include antimicrobial activity, larvicidal activity, hepatoprotective activity, nematicidal and mosquito repellent potential and antihyperlipidaemic properties.In this study, the authors compare the composition of the volatile fractions of A. graveolens collected in natural populations in Portugal and Italy and evaluate their potential as antifungal agents.The composition of the volatile oils obtained by hydrodistillation and their antifungal activity are reported. The oils were analysed by gas chromatography–flame ionisation detector and gas chromatography–mass spectrometry methods and their composition were compared with that of the volatile extracts isolated by supercritical CO2. A chemical variability in the extracts depending on the origin of the plants and on the extraction method was observed. The results showed the presence of sedanenolide, neocnidilide and neophytadiene as main components. The minimal inhibitory concentration (MIC) and the minimal lethal concentration were used to evaluate the antifungal activity of the oils against Candida albicans, Candida tropicalis, Candida krusei, Candida guilliermondii, Candida parapsilosis, Cryptococcus neoformans, Trichophyton rubrum, Trichophyton mentagrophytes, T. mentagrophytes var. interdigitale, Trichophyton verrucosum, Microsporum canis, Microsporum gypseum, Epidermophyton floccosum, Aspergillus niger, Aspergillus fumigatus and Aspergillus flavus. The oil from Italy rich in neophytadiene is the more active, with MIC values of 0.04–0.64 µL mL−1. Our results show that A. graveolens volatile extracts may be useful in the clinical treatment of fungal diseases.

State of the art diagnostic of mold diseases: a practical guide for clinicians

The epidemiology of fungal diseases changed, and molds have been increasingly associated with high mortality in severe immunocompromised patients. Invasive mold diseases may originate from the airborne conidia through inhalation or inoculation in skin fissures associated with indwelling catheters, wounds, burns, or onychomycosis. The diagnosis and treatment of fungal diseases is problematic and raises considerable challenges. Diagnosis of invasive mold diseases includes several methodologies, of which the most commonly used are the cultural methods, antigen testing, nucleic acid detection, and radiological imaging. Galactomannan and (1 → 3)-β-D-glucan detection significantly improved mold diagnosis in the last decade. Several molecular strategies have been proposed over the years but no consensus was achieved for standardized protocols or cut-off values. Recently, the first commercially available molecular assay for detection of Aspergillus was tested and the results were highly reproducible. In addition, blood cultures may also be helpful for invasive aspergillosis by following a novel procedure for the recovery of Aspergillus spp. from blood cultures. The association of distinct diagnostic methods, particularly molecular tests, galactomannan, and/or (1 → 3)-β-D-glucan detection, may provide earlier and more sensitive diagnosis of mold diseases and be indicative for early antifungal treatment. Accurate routine use of diagnostic tests can be cost-effective for laboratories and be of great value to patients.

Increased incidence of cutaneous squamous cell carcinoma in lung transplant recipients taking long-term voriconazole

Voriconazole has been used for prevention and treatment of fungal infections in patients after lung transplantation. We postulate that long-term use of voriconazole may increase the risk of squamous cell carcinoma of the skin in these patients. The study included 120 patients who received lung transplantation at UC San Diego Health System between July 2000 and June 2006. All patients received a similar initial immunosuppression regimen, and 43 (35.8%) received voriconazole for treatment or prophylaxis for fungal diseases. In this retrospective study, we compared the incidence of squamous cell carcinoma in lung transplant recipients with or without voriconazole use. Squamous cell carcinomas developed in 39.5% of patients (17 of 43) who received voriconazole for prophylaxis or treatment of fungal disease, compared with 19.5% (15 of 77) who did not receive voriconazole (p = 0.03). Four patients died of metastatic squamous cell carcinoma, all in the voriconazole group. Multiple logistic regression analysis showed older age at the time of transplant (odds ratio [OR], OR (95% CI) 2.8 (1.5-5.5)), skin cancer pre-transplant (OR, 11.0 (1.76-68.4), and longer voriconazole therapy (OR, 1.8 (1.3-2.6)) were independent risk factors for development of skin cancer after transplant. Our results suggest that long-term use of voriconazole may be associated with development of cutaneous squamous cell carcinoma in patients after lung transplant. Greater clinical aggressiveness of skin cancer was also noted in these patients.

Intelligent multi-sensor system for the detection and treatment of fungal diseases in arable crops

The development of a ground-based real-time remote sensing system that can be carried by tractors or robotic platforms is described. This prototype system makes possible the detection of plant diseases in arable crops automatically at an early stage of disease development and during field operations. The methodology uses differences in reflectance between healthy and diseased plants. Hyperspectral reflectance and multi-spectral imaging techniques were developed for simultaneous acquisition in the same canopy. Experimental platforms were constructed, and the advantage of using sensor fusion was demonstrated. An intelligent multi-sensor fusion decision system based on neural networks was developed to predict the presence of diseases or plant stresses, in order to treat the diseases in a spatially variable way. A robust multi-sensor platform integrating optical sensing, GPS (Geostationary Positioning System) and a data processing unit was constructed and calibrated. The functionality of automatic disease sensing and detection devices is crucial in order to conceive a site-specific spraying strategy against fungal foliar diseases. Field tests were carried out to optimise the functioning of the multi-sensor disease detection device. An overview is provided on how disease presence data are processed in order to enable an automatic site-specific spraying strategy in winter wheat. Furthermore, mapping of diseases based on automated optical sensing and intelligent prediction provide a spatially variable recommendation for spraying.

Treatment of Aspergillus species infection in reptiles with itraconazole at metabolically scaled doses

THERE is little information in the literature on the treatment of fungal diseases, particularly aspergillosis, with itraconazole in reptiles ([Heatley and others 2001][1]). The use of itraconazole in reptiles has largely been extrapolated from birds ([Gamble and others 1997][2]) or mammals ([Heatley

Two-Component Signal Transduction Proteins as Potential Drug Targets in Medically Important Fungi

Two-Component Signal Transduction Proteins as Potential Drug Targets in Medically Important Fungi

The University Network of Education and Technical Support of Treatment of Fungal Diseases for Dermatologists

In July 2007, information on the current status of mycological examinations in Japanese university clinics and requests for a university network system was gathered by a questionnaire completed by 98 of 112 professors or directors of those clinics. A summary of the findings follows: only 9% of the hospitals performed fungal culture studies for all or most cases, indicating a drop of 7% from 2000 (16% in 2000, reported by Kasai) . Also, just 55% of relevant departments maintained the ability to identify most or all clinical isolates in-house, which down 27% from 2000 (83% in 2000, reported by Kasai). These findings indicate that mycological diagnoses by many departments have been rapidly decreasing. Eighty-nine percent of respondents indicated a desire for some help from the university network including: basic training in medical mycology of young doctors (senior residents in university hospitals); aid in diagnosing rare fungal infections; and support in obtaining knowledge and new technologies. The basic training of senior residents in each department is not possible in the network system so each department is required to take responsibility for training their own. However, a project of an advanced course at the leader level, which educates the person in charge of each department, may be possible in the network system. Employing this would make it realistic for the educated leaders to train the senior residents in their departments.

Mixed micellar nanoparticle of amphotericin b and poly styrene-block-poly ethylene oxide reduces nephrotoxicity but retains antifungal activity

Mixed micellar nanoparticle consisting of amphotericin B (AmB) and poly styrene-block-poly ethylene oxide (PS-block-PEO) was prepared by high pressure homogenizer. Nephrotoxicity of the nanoparticle was investigated along with antifungal activity and self-aggregation status of the drug in the nanoparticle. Nephrotoxicity was markedly reduced when AmB was intravenously administered to rats as mixed micellar nanoparticle with PS-block-PEO in terms of transmission electron microscopy of tubular cells and creatinine clearance. Antifungal activity of AmB was not altered when the drug was in the form of mixed micellar nanoparticle compared to both conventional formulation and AmB micelle treated by same procedure without PS-block-PEO. Self-aggregation status of AmB molecules revealed monomeric in the mixed micellar nanoparticle with PS-block-PEO up to the therapeutic level of the drug (1-3 mM). The reduced nephrotoxicity of AmB in mixed micellar nanoparticle may be associated with the existence of the drug as monomeric form in the nanoparticle. Based on our result, formulation of AmB as mixed micellar nanoparticle with PS-block-PEO may be a promising alternative for the treatment of fungal diseases in patients who are at risk of renal dysfunction.

In Vitro Activity (MIC and MFC) of Voriconazole, Amphotericin B, and Itraconazole Against 192 Filamentous Fungi: The GISIA-2 Study

We evaluated the In Vitro activity of voriconazole, amphotericin B, and itraconazole against 192 clinical mould isolates recovered in twenty Italian microbiology laboratories. The vast majority of isolates belonged to the genus Aspergillus (94.2%) with A. fumigatus (58.3%) being the most frequently isolated species. Antifungal susceptibility testing was performed using the broth microdilution method defined by the CLSI M38-A standard, and results were compared to those obtained with Sensititre panels. Aspergillus flavus ATCC 204304 was employed as reference strain and results were within all expected ranges. Voriconazole' activity against the 192 mould isolates was comparable to that of amphotericin B and itraconazole: voriconazole MIC90 (CLSI 1 μg/ml, Sensititre 1 μg/ml), itraconazole MIC90 (CLSI 0.5 μg/ml, Sensititre 0.5 μg/ml), amphotericin B MIC90 (CLSI 1 μg/ml, Sensititre 1 μg/ml). In conclusion, these in vitro data highlight voriconazole's broad spectrum activity against filamentous fungi and support its use as a first line agent for the treatment of fungal diseases.

Phosphorylation of Candida glabrata ATP-binding Cassette Transporter Cdr1p Regulates Drug Efflux Activity and ATPase Stability

Fungal ATP-binding cassette transporter regulation was investigated using Candida glabrata Cdr1p and Pdh1p expressed in Saccharomyces cerevisiae. Rephosphorylation of Pdh1p and Cdr1p was protein kinase A inhibitor-sensitive but responded differentially to Tpk isoforms, stressors, and glucose concentration. Cdr1p Ser(307), which borders the nucleotide binding domain 1 ABC signature motif, and Ser(484), near the membrane, were dephosphorylated on glucose depletion and independently rephosphorylated during glucose exposure or under stress. The S484A enzyme retained half the wild type ATPase activity without affecting azole resistance, but the S307A enzyme was unstable to plasma membrane isolation. Studies of pump function suggested conformational interaction between Ser(484) and Ser(307). An S307A/S484A double mutant, which failed to efflux the Cdr1p substrate rhodamine 6G, had a fluconazole susceptibility 4-fold greater than the Cdr1p expressing strain, twice that of the S307A mutant, but 64-fold less than the control null strain. Stable intragenic suppressors indicative of homodimer nucleotide binding domain 1-nucleotide binding domain 1 interactions partially restored rhodamine 6G pumping and increased fluconazole and rhodamine 6G resistance in the S307A/S484A mutant. Nucleotide binding domain 1 of Cdr1p is a sensor of important physiological stimuli.

Characterization of sphingolipids from mycopathogens: factors correlating with expression of 2-hydroxy fatty acyl (E)-Delta 3-unsaturation in cerebrosides of Paracoccidioides brasiliensis and Aspergillus fumigatus.

Significant differences exist between mammals and fungi with respect to glycosphingolipid (GSL) structure and biosynthesis. Thus, these compounds, as well as the cellular machinery regulating their expression, have considerable potential as targets for the diagnosis and treatment of fungal diseases. In this study, the major neutral GSL components extracted from both yeast and mycelium forms of the thermally dimorphic mycopathogen Paracoccidioides brasiliensis were purified and characterized by 1H and 13C NMR spectroscopy, ESI-MS and ESI-MS/CID-MS, and GC-MS. The major GSLs of both forms were identified as beta-glucopyranosylceramides (GlcCer) having (4E, 8E)-9-methyl-4,8-sphingadienine as long chain base in combination with either N-2'-hydroxyoctadecanoate or N-2'-hydroxy-(E)-3'-octadecenoate. The mycelium form GlcCer had both fatty acids in a approximately 1:1 ratio, while that of the yeast form had on average only approximately 15% of the (E)-Delta 3-unsaturated fatty acid. Cerebrosides from two strains of Aspergillus fumigatus (237 and ATCC 9197) expressing both GalCer and GlcCer were also purified and characterized by similar methods. The GalCer fractions were found to have approximately 70% and approximately 90% N-2'-hydroxy-(E)-3'-octadecenoate, respectively, in the two strains. In contrast, the GlcCer fractions had N-2'-hydroxy-(E)-3'-octadecenoate at only approximately 20 and approximately 50%, respectively. The remainder in all cases was the saturated 2-OH fatty acid, which has not been previously reported in cerebrosides from A. fumigatus. The availability of detailed structures of both glycosylinositol phosphorylceramides [Levery, S. B., Toledo, M. S., Straus, A. H., and Takahashi, H. K. (1998) Biochemistry 37, 8764-8775] and cerebrosides from P. brasiliensis revealed parallel quantitative differences in expression between yeast and mycelium forms, as well as a striking general partitioning of ceramide structure between the two classes of GSLs. These results are discussed with respect to possible functional roles for fungal sphingolipids, particularly as they relate to the morphological transitions exhibited by P. brasiliensis.

Antifungal Activity of Aqueous Extract of Dormant Fruits of Hyphaene thebaica (Palmae)

Aqueous extract of the dormant fruits derived from Hyphaene thebaica was tested for in vitro antifungal activity using the agar dilution method. The extract was found to produce significant antifungal activity against a wide range of fungal isolates including Candida albicans, Microsporum gypseum, Trichophyton rubrum, Mucor sp., Fusarium solani and Aspergillus niger. The minimum inhibitory concentration of the extract ranged between 3.1 to 25% v/v. The dermatophytic fungi (Microsporum gypseum and Trichophyton rubrum) were more susceptible to the antifungal effects of the extract (MIC 3.1) while Candida albicans found to be least susceptible (MIC 25). The findings indicate that this material may have value in the treatment of fungal diseases, pending the results of further studies.

Patent Evaluation: Bridged Cyclic Ketal Derivatives as Squalene Synthetase Inhibitors

SummaryNovelty: Bridged cyclic ketals are described which are claimed to inhibit squalene synthase, thereby having potential in the treatment of fungal diseases, hypercholesterolaemia and hyperlipoproteinaemia.Biology: Squalene synthase inhibitory activity was determined by incubation of the compound with [2-14C]-farnesylpyrophosphate and homogenized rat liver, and measurement of the concentration of [14C] squalene produced. IC50 (50% inhibition) values were < 100 nM for forty-four compounds. In vitro activity against Candida albicans was also included.Chemistry: Several cyclic ketals, obtained by fermentation, were chemically modified to produce novel derivatives. Over sixty intermediates and sixty-eight compounds are fully exemplified. Over twenty compounds are specifically claimed, including [1S-[1α(4S*,5S*),3α,4β,5α,6α(2E,4R*,6R*)7β]] 1-(4-hydroxy-5-methyl-3-methylene-6-phenylhexyl)- 4,6,7-trihydxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid-6-(4,6-dimethyl-2-octenoate).Structure:

Special features of the clinical use of oral terbinafine in the treatment of fungal diseases.

Terbinafine (Lamisil) is an antifungal drug, belonging to a class of drugs called the allylamines, which has recently become available for clinical use. This is a report of four special features which emerged during evaluation of the systemic use of orally administered terbinafine in the treatment of 2500 patients during the last 5 years. These features include: (i) distribution of terbinafine in skin, hair and nail tissue; (ii) use in short-duration treatment of chronic tinea pedis and onychomycosis; (iii) use in patients with serious infections often associated with local or generalized immunological defects; and (iv) tolerability and safety of the drug. The diffusion of terbinafine into thickened, chronically infected tissue and into nails, and its recognized fungicidal action are the most likely features responsible for its success in the treatment of chronic fungal diseases, including those with immunological defects. Terbinafine is well tolerated, particularly when compared with other available systemic antifungal drugs.