Asunto(s)
Antibacterianos/química , Aspergillus/química , Benzopiranos/química , Antibacterianos/biosíntesis , Antibacterianos/farmacología , Antifúngicos/biosíntesis , Antifúngicos/química , Antifúngicos/farmacología , Benzopiranos/farmacología , Candida albicans/efectos de los fármacos , Fermentación , Espectroscopía de Resonancia Magnética , Conformación Molecular , Saccharomyces cerevisiae/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacosRESUMEN
Four new caryophyllene derivatives, Sch 725432 (1), Sch 601253 (2), Sch 601254 (3), and Sch 725434 (4), were isolated from the fungal fermentation broth of Chrysosporium pilosum by reversed-phase HPLC purification. The structure elucidation of trioxygenated caryophyllenes 1-4 was accomplished on the basis of spectroscopic data interpretation. Sch 725434 (4) possesses a dihydrofuran-3-one ring, forming a tricyclic ring skeleton, which represents an unprecedented ring skeleton for the caryophyllene-type of sesquiterpenes. Compounds 1-4 were evaluated for their antifungal activity.
Asunto(s)
Chrysosporium/química , Saccharomyces cerevisiae/efectos de los fármacos , Sesquiterpenos/aislamiento & purificación , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Antifúngicos/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Sesquiterpenos Policíclicos , Sesquiterpenos/química , Sesquiterpenos/farmacologíaRESUMEN
Posaconazole (SCH 56592) is a novel triazole antifungal drug that is marketed in Europe and the United States under the trade name 'Noxafil' for prophylaxis against invasive fungal infections. SCH 56592 was discovered as a possible active metabolite of SCH 51048, an earlier lead. Initial studies have shown that serum concentrations determined by a microbiological assay were higher than those determined by HPLC from animals dosed with SCH 51048. Subsequently, several animals species were dosed with (3)H-SCH 51048 and the serum was analyzed for total radioactivity, SCH 51048 concentration and antifungal activity. The antifungal activity was higher than that expected based on SCH 51048 serum concentrations, confirming the presence of active metabolite(s). Metabolite profiling of serum samples at selected time intervals pinpointed the peak that was suspected to be the active metabolite. Consequently, (3)H-SCH 51048 was administered to a large group of mice, the serum was harvested and the metabolite was isolated by extraction and semipreparative HPLC. LC-MS/MS analysis suggested that the active metabolite is a secondary alcohol with the hydroxyl group in the aliphatic side chain of SCH 51048. All corresponding monohydroxylated diastereomeric mixtures were synthesized and characterized. The HPLC retention time and LC-MS/MS spectra of the diastereomeric secondary alcohols of SCH 51048 were similar to those of the isolated active metabolite. Finally, all corresponding individual monohydroxylated diasteriomers were synthesized and evaluated for in vitro and in vivo antifungal potencies, as well as pharmacokinetics. SCH 56592 emerged as the candidate with the best overall profile.
Asunto(s)
Antifúngicos/análisis , Antifúngicos/farmacocinética , Espectrometría de Masas , Triazoles/análisis , Triazoles/farmacocinética , Animales , Antifúngicos/sangre , Cromatografía Líquida de Alta Presión , Perros , Diseño de Fármacos , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos , Conejos , Triazoles/sangreRESUMEN
The interaction of posaconazole and caspofungin was evaluated in concomitant treatment of Aspergillus fumigatus (two strains) or A. flavus (one strain) systemic infections in immunocompetent mice. Survival curves for mice treated with the combinations were compared statistically with those for mice treated with the component monotherapies. No antagonism was observed.
Asunto(s)
Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Aspergillus flavus/efectos de los fármacos , Aspergillus fumigatus/efectos de los fármacos , Péptidos Cíclicos/uso terapéutico , Triazoles/uso terapéutico , Animales , Aspergilosis/microbiología , Caspofungina , Interacciones Farmacológicas , Quimioterapia Combinada , Equinocandinas , Lipopéptidos , Masculino , Ratones , Pruebas de Sensibilidad MicrobianaRESUMEN
A new 5-alkenylresorcinol Sch725681 (1) was isolated and identified from the culture of an Aspergillus sp. The structure elucidation of 1 was accomplished based on extensive NMR spectroscopic analyses. Compound 1 showed inhibitory activity against Saccharomyces cerevisiae (PM503) and Candida albicans (C43) with MICs of 16 and 64 microg/ml, respectively.
Asunto(s)
Antifúngicos/aislamiento & purificación , Aspergillus/metabolismo , Resorcinoles/aislamiento & purificación , Antifúngicos/química , Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Resorcinoles/química , Resorcinoles/farmacología , Saccharomyces cerevisiae/efectos de los fármacosRESUMEN
As part of a detailed study, the syntheses, biological activities, and pharmacokinetic properties of hydroxylated analogues of the previously described broad spectrum antifungal agents, Sch 51048 (1), Sch 50001 (3), and Sch 50002 (4), are described. Based on an overall superior profile, one of the alcohols, Sch 56592 (2), was selected for clinical studies.
Asunto(s)
Antifúngicos/farmacología , Química Farmacéutica/métodos , Triazoles/química , Triazoles/síntesis química , Triazoles/farmacología , Alcoholes , Animales , Antifúngicos/química , Aspergilosis/tratamiento farmacológico , Candidiasis/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Haplorrinos , Humanos , Inmunosupresores/farmacología , Ratones , Modelos Químicos , Factores de Tiempo , Triazoles/farmacocinéticaRESUMEN
Systemic coccidioidomycosis was diagnosed in a 4-year-old male chimpanzee (Pan troglodytes) with ascites and failure to thrive. Physical examination, laboratory and radiological studies, and exploratory laparotomy showed signs of systemic fungal infection that included penetration into the central nervous system (CNS). Serum and cerebrospinal fluid (CSF) titres, along with ascites cytology findings, confirmed the presence of Coccidioides immitis. However, the organism could not be cultured from the CSF. Treatment with fluconazole 10 mg kg(-1) daily for 6 months was not associated with clinical improvement. Subsequent treatment with posaconazole 50 mg kg(-1) daily for approximately 24 months resulted in negative serum titres and improved clinical status. Illness not directly related to the C. immitis infection caused the chimpanzee's deterioration and eventual killing. Histological examination performed during necropsy provided no evidence of coccidioidomycosis; however, a positive C. immitis serum antibody titre was noted. The successful suppression of coccidioidomycosis observed in this chimpanzee suggests that posaconazole may have a role in the treatment of CNS infections caused by susceptible fungi.
Asunto(s)
Antifúngicos/uso terapéutico , Enfermedades del Simio Antropoideo/tratamiento farmacológico , Coccidioides/aislamiento & purificación , Coccidioidomicosis/veterinaria , Pan troglodytes , Triazoles/uso terapéutico , Animales , Anticuerpos Antifúngicos/sangre , Antifúngicos/administración & dosificación , Enfermedades del Simio Antropoideo/microbiología , Sangre/microbiología , Infecciones Fúngicas del Sistema Nervioso Central/microbiología , Infecciones Fúngicas del Sistema Nervioso Central/veterinaria , Líquido Cefalorraquídeo/microbiología , Coccidioides/efectos de los fármacos , Coccidioidomicosis/complicaciones , Coccidioidomicosis/tratamiento farmacológico , Coccidioidomicosis/patología , Fluconazol/administración & dosificación , Fluconazol/uso terapéutico , Laparoscopía , Masculino , Triazoles/administración & dosificaciónRESUMEN
A new macrolide Sch725674 (1) was isolated and identified from the culture of an Aspergillus sp. The structure elucidation of 1 was accomplished based on extensive NMR spectroscopic analyses. Compound 1 showed inhibitory activity against Saccharomyces cerevisiae (PM503) and Candida albicans (C43) with MICs of 8 and 32 microg/ml, respectively.
Asunto(s)
Antifúngicos/farmacología , Aspergillus/química , Macrólidos/farmacología , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Candida albicans/efectos de los fármacos , Macrólidos/química , Macrólidos/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Saccharomyces cerevisiae/efectos de los fármacosRESUMEN
The in vitro activities of three new triazoles were determined and compared to those of itraconazole and fluconazole against 306 clinical isolates of Blastomyces dermatitidis, Cladophialophora carrionii, Coccidioides immitis, Fonsecaea pedrosoi, Fusarium spp., Histoplasma capsulatum, Paecilomyces lilacinus, Pseudallescheria boydii and Sporothrix schenckii. Minimum inhibitory concentrations (MIC) were determined by a broth macrodilution method of the National Committee for Clinical Laboratory Standards M38-A procedure. Itraconazole (geometric mean MIC, 0.16-0.65 microg/ml), voriconazole (geometric mean MIC, 0.18-1.44 microg/ml), ravuconazole (geometric mean MIC, 0.18-1.09 microg/ml), and posaconazole (geometric mean MIC, 0.18-1.38 microg/ml), had relatively uniform values showing potent in vitro inhibitory activity against B. dermatitidis, C. carrionii, C. immitis, F. pedrosoi, H. capsulatum, and S. schenckii. The in vitro activity was variable with strains of P. boydii, P. lilacinus and Fusarium spp.
Asunto(s)
Hongos/efectos de los fármacos , Triazoles/farmacología , Antifúngicos/farmacología , Hongos/aislamiento & purificación , Humanos , Pruebas de Sensibilidad Microbiana , Micosis/microbiología , Pirimidinas/farmacología , Especificidad de la Especie , Tiazoles/farmacología , VoriconazolRESUMEN
A new microbial metabolite Sch 725424 (1) was isolated from the culture of Kitasatospora sp. The structure elucidation of 1 was accomplished based on NMR spectroscopic analyses as well as extensive structure elucidation of its dehydration product Sch 725428 (2). Compound 1 showed inhibitory activity against Staphylococcus aureus with MIC values 1-2 microg/ml, and also displayed weak antifungal activity against Saccharomyces cerevisiae (PM503) with an MIC 32 microg/ml.
Asunto(s)
Amidas/química , Amidas/metabolismo , Antibacterianos/biosíntesis , Antibacterianos/química , Furanos/química , Furanos/metabolismo , Polienos/química , Polienos/metabolismo , Streptomycetaceae/metabolismo , Amidas/farmacología , Antibacterianos/farmacología , Antifúngicos/química , Antifúngicos/metabolismo , Antifúngicos/farmacología , Fermentación , Furanos/farmacología , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Polienos/farmacología , Saccharomyces cerevisiae/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacosRESUMEN
OBJECTIVES: The in vitro antifungal activity of posaconazole was compared with that of fluconazole and amphotericin B. MATERIALS AND METHODS: A microdilution method (M27-A2) was used with 331 clinical yeast isolates. RESULTS: The geometric mean MICs of posaconazole, fluconazole and amphotericin B were 0.16, 0.91 and 0.15 mg/L, respectively. Posaconazole was markedly more active than fluconazole and was active against 9/11 fluconazole-resistant Candida albicans, and five Candida glabrata had an MIC of posaconazole of 16 mg/L. CONCLUSIONS: These data indicate that posaconazole is a potentially effective antifungal agent for the treatment of mycoses caused by yeasts.
Asunto(s)
Anfotericina B/farmacología , Antifúngicos/farmacología , Candida/efectos de los fármacos , Candidiasis Bucal/microbiología , Triazoles/farmacología , Fluconazol/farmacología , Humanos , Pruebas de Sensibilidad MicrobianaRESUMEN
The interaction of posaconazole and amphotericin B was evaluated in concomitant treatment of Candida albicans systemic infections in immunocompetent mice by using four strains of C. albicans with different susceptibilities to fluconazole. Posaconazole and amphotericin B were each tested at four dose levels alone and in all possible combinations against each C. albicans strain. Survival curves of mice treated with combinations of posaconazole and amphotericin B were statistically compared with those of mice treated with the component monotherapies. Of the 64 total combinations evaluated against the C. albicans strains (16 combinations per strain), 20.3% were more effective in prolonging mouse survival than both of the monotherapies, 45.3% were more effective than one of the monotherapies, and 32.8% were similar to both monotherapies. No evidence of antagonism was observed between posaconazole and amphotericin B in this mouse model, consistent with in vitro results against the same strains.
Asunto(s)
Anfotericina B/farmacología , Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Triazoles/farmacología , Anfotericina B/uso terapéutico , Animales , Antifúngicos/uso terapéutico , Candidiasis/microbiología , Candidiasis/mortalidad , Interacciones Farmacológicas , Masculino , Ratones , Análisis de Supervivencia , Triazoles/uso terapéuticoAsunto(s)
Antraciclinas , Antibacterianos , Antifúngicos , Micromonospora/metabolismo , Antraciclinas/química , Antraciclinas/aislamiento & purificación , Antraciclinas/farmacología , Antibacterianos/farmacología , Antifúngicos/farmacología , Hongos/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Pruebas de Sensibilidad MicrobianaRESUMEN
Posaconazole (POS; SCH 56592) is a novel triazole that is active against a wide variety of fungi, including fluconazole-resistant Candida albicans isolates and fungi that are inherently less susceptible to approved azoles, such as Candida glabrata. In this study, we compared the effects of POS, itraconazole (ITZ), fluconazole (FLZ), and voriconazole (VOR) on sterol biosynthesis in strains of C. albicans (both azole-sensitive and azole-resistant strains), C. glabrata, Aspergillus fumigatus, and Aspergillus flavus. Following exposure to azoles, nonsaponifiable sterols were extracted and resolved by liquid chromatography and sterol identity was confirmed by mass spectroscopy. Ergosterol was the major sterol in all but one of the strains; C. glabrata strain C110 synthesized an unusual sterol in place of ergosterol. Exposure to POS led to a decrease in the total sterol content of all the strains tested. The decrease was accompanied by the accumulation of 14alpha-methylated sterols, supporting the contention that POS inhibits the cytochrome P450 14alpha-demethylase enzyme. The degree of sterol inhibition was dependent on both dose and the susceptibility of the strain tested. POS retained activity against C. albicans isolates with mutated forms of the 14alpha-demethylase that rendered these strains resistant to FLZ, ITZ, and VOR. In addition, POS was a more potent inhibitor of sterol synthesis in A. fumigatus and A. flavus than either ITZ or VOR.
Asunto(s)
Antifúngicos/farmacología , Aspergillus flavus/metabolismo , Aspergillus fumigatus/metabolismo , Candida glabrata/metabolismo , Inhibidores Enzimáticos del Citocromo P-450 , Inhibidores Enzimáticos/farmacología , Oxidorreductasas/antagonistas & inhibidores , Triazoles/farmacología , Aspergillus flavus/efectos de los fármacos , Aspergillus fumigatus/efectos de los fármacos , Azoles/farmacología , Candida glabrata/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Ergosterol/metabolismo , Cromatografía de Gases y Espectrometría de Masas , Pruebas de Sensibilidad Microbiana , Esterol 14-DesmetilasaAsunto(s)
Indoles/química , Micromonospora/química , Piperazinas/química , Bacterias/efectos de los fármacos , Medios de Cultivo , Fermentación , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Saccharomyces cerevisiae/efectos de los fármacos , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Using an inhalation model of pulmonary aspergillosis, we observed modest differences in the survival rates of mice treated with granulocyte colony-stimulating factor (G-CSF) and posaconazole (POS) and those treated with POS alone. This finding is in contrast to a previous report that suggested that G-CSF had a significant antagonistic effect on the antifungal activity of POS.
Asunto(s)
Antifúngicos/uso terapéutico , Aspergilosis Broncopulmonar Alérgica/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Triazoles/uso terapéutico , Animales , Aspergilosis Broncopulmonar Alérgica/microbiología , Aspergilosis Broncopulmonar Alérgica/mortalidad , Quimioterapia Combinada , Pulmón/microbiología , Masculino , Ratones , Análisis de SupervivenciaRESUMEN
Real-time quantitative PCR was used to measure expression levels of genes encoding efflux pumps, ERG11 and two control genes, ACT1 and PMA1, in a collection of 14 fluconazole-susceptible Candida albicans isolates. For each gene, average expression levels and variations within the population were determined. These values were then used as reference points to make predictions about the molecular basis of resistance in 38 clinical isolates (the majority of which were resistant to fluconazole) obtained from 18 patients treated with posaconazole for refractory oropharyngeal candidiasis. For each of the 38 isolates, the expression levels of genes encoding efflux pumps, ERG11 and the control genes, were measured as above. Comparison of the two data sets revealed that expression of ACT1 and PMA1 did not vary significantly between the two sets of isolates. In contrast, MDR1, ERG11, CDR1, and CDR2 were overexpressed in 3, 4, 14, and 35, respectively, of the isolates from patients treated with azoles. In addition to these changes, the patient isolates all had at least one and often multiple missense mutations in ERG11. Select ERG11 alleles were expressed in Saccharomyces cerevisiae; all of the alleles tested conferred reduced susceptibility to fluconazole. Despite both the increases in pump expression and the ERG11 mutations, only one of the patient isolates exhibited a large decrease in posaconazole susceptibility.
Asunto(s)
Antifúngicos/farmacología , Azoles/farmacología , Candida albicans/efectos de los fármacos , Candida albicans/genética , Actinas/genética , Antifúngicos/uso terapéutico , Candidiasis Bucal/tratamiento farmacológico , Candidiasis Bucal/microbiología , Clonación Molecular , Sistemas de Computación , ADN de Hongos/genética , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Farmacorresistencia Fúngica , Proteínas Fúngicas/genética , Regulación Fúngica de la Expresión Génica/genética , Pruebas de Sensibilidad Microbiana , Mutación/genética , Orofaringe/microbiología , ATPasas de Translocación de Protón/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas de Saccharomyces cerevisiae/genética , Especificidad de la Especie , Transcripción Genética , Triazoles/farmacología , Triazoles/uso terapéuticoRESUMEN
Immunocompetent (nu/+) and athymic (nu/nu) BALB/c mice were infected intravenously with Wangiella dermatitidis and treated with posaconazole. Posaconazole reduced the counts in tissues and prolonged survival. Of particular interest, posaconazole reduced the counts of this neurotropic pathogen in the brain.
Asunto(s)
Antifúngicos/uso terapéutico , Exophiala , Micosis/tratamiento farmacológico , Triazoles/uso terapéutico , Animales , Encéfalo/microbiología , Recuento de Colonia Microbiana , Huésped Inmunocomprometido , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Micosis/microbiología , Análisis de SupervivenciaRESUMEN
Posaconazole and/or amphotericin B was given to mice pretreated with a steroid and then infected by inhalation of Aspergillus flavus conidia. Two laboratories conducted studies using almost identical protocols to evaluate both survival and lung tissue burdens 8 days after infection. The results of the in vivo studies performed at both laboratories were consistent. We found that (i). up to 5 mg of amphotericin B per kg of body weight was poorly effective in treating invasive aspergillosis; (ii). posaconazole at 2 or 10 mg/kg/dose prolonged survival and reduced lung tissue CFU; and (iii). there was generally no antagonistic interaction of the drugs in combination, even when the experiments were designed to maximize the likelihood of antagonism. These studies do not confirm the antagonistic interaction of triazoles and polyenes reported by others.