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1.
Antimicrob Agents Chemother ; 60(12): 7115-7127, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27645246

RESUMO

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.


Assuntos
Antifúngicos/farmacologia , Criptococose/tratamento farmacológico , Fluconazol/farmacologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Animais , Candida/efeitos dos fármacos , Candida/genética , Caspofungina , Celecoxib/química , Cryptococcus neoformans/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Farmacorresistência Fúngica/efeitos dos fármacos , Sinergismo Farmacológico , Equinocandinas/farmacologia , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Lipopeptídeos/farmacologia , Masculino , Camundongos Endogâmicos , Testes de Sensibilidade Microbiana , Pneumocystis/efeitos dos fármacos , Pirazóis/química , Saccharomyces cerevisiae/efeitos dos fármacos , Sulfonamidas/química
2.
Int J Antimicrob Agents ; 47(4): 286-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26976780

RESUMO

In this study, 27 clinical isolates of Candida glabrata with voriconazole (VRC) minimum inhibitory concentrations (MICs) ranging from ≤0.03 µg/mL to 8 µg/mL were tested to determine whether in vitro data are predictive of in vivo efficacy. The efficacy of VRC administered at 40 mg/kg was assayed in a neutropenic murine model of disseminated infection by C. glabrata. The reduction in fungal tissue burden in the kidneys was used as a marker of treatment efficacy. VRC reduced the fungal tissue burden in mice infected with strains that had MICs below the epidemiological cut-off value (ECV) of 0.25 µg/mL. Variable efficacy of VRC was obtained when the MIC equalled the ECV, and VRC was ineffective when the MIC exceeded the ECV. These results suggest that the use of in vitro data could be useful to predict the outcome for infections by this fungus.


Assuntos
Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida glabrata/efeitos dos fármacos , Candidíase/tratamento farmacológico , Voriconazol/farmacologia , Voriconazol/uso terapêutico , Animais , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Rim/microbiologia , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Resultado do Tratamento
3.
Antimicrob Agents Chemother ; 59(12): 7249-54, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26369964

RESUMO

Coccidioidomycosis, or valley fever, is a growing health concern endemic to the southwestern United States. Safer, more effective, and more easily administered drugs are needed especially for severe, chronic, or unresponsive infections. The novel fungal CYP51 inhibitor VT-1161 demonstrated in vitro antifungal activity, with MIC50 and MIC90 values of 1 and 2 µg/ml, respectively, against 52 Coccidioides clinical isolates. In the initial animal study, oral doses of 10 and 50 mg/kg VT-1161 significantly reduced fungal burdens and increased survival time in a lethal respiratory model in comparison with treatment with a placebo (P < 0.001). Oral doses of 25 and 50 mg/kg VT-1161 were similarly efficacious in the murine central nervous system (CNS) model compared to placebo treatment (P < 0.001). All comparisons with the positive-control drug, fluconazole at 50 mg/kg per day, demonstrated either statistical equivalence or superiority of VT-1161. VT-1161 treatment also prevented dissemination of infection from the original inoculation site to a greater extent than fluconazole. Many of these in vivo results can be explained by the long half-life of VT-1161 leading to sustained high plasma levels. Thus, the efficacy and pharmacokinetics of VT-1161 are attractive characteristics for long-term treatment of this serious fungal infection.


Assuntos
Inibidores de 14-alfa Desmetilase/farmacologia , Antifúngicos/farmacologia , Coccidioides/efeitos dos fármacos , Coccidioidomicose/tratamento farmacológico , Fluconazol/farmacologia , Fungemia/prevenção & controle , Piridinas/farmacologia , Tetrazóis/farmacologia , Inibidores de 14-alfa Desmetilase/sangue , Inibidores de 14-alfa Desmetilase/farmacocinética , Animais , Antifúngicos/sangue , Antifúngicos/farmacocinética , Coccidioides/enzimologia , Coccidioides/crescimento & desenvolvimento , Coccidioidomicose/microbiologia , Coccidioidomicose/mortalidade , Coccidioidomicose/patologia , Modelos Animais de Doenças , Feminino , Fluconazol/sangue , Fluconazol/farmacocinética , Proteínas Fúngicas/antagonistas & inibidores , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Fungemia/microbiologia , Fungemia/mortalidade , Fungemia/patologia , Meia-Vida , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Piridinas/sangue , Piridinas/farmacocinética , Esterol 14-Desmetilase/genética , Esterol 14-Desmetilase/metabolismo , Análise de Sobrevida , Tetrazóis/sangue , Tetrazóis/farmacocinética , Resultado do Tratamento
4.
mBio ; 6(3): e00647, 2015 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-26106079

RESUMO

UNLABELLED: Recent estimates suggest that >300 million people are afflicted by serious fungal infections worldwide. Current antifungal drugs are static and toxic and/or have a narrow spectrum of activity. Thus, there is an urgent need for the development of new antifungal drugs. The fungal sphingolipid glucosylceramide (GlcCer) is critical in promoting virulence of a variety of human-pathogenic fungi. In this study, we screened a synthetic drug library for compounds that target the synthesis of fungal, but not mammalian, GlcCer and found two compounds [N'-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative, 3-bromo-N'-(3-bromo-4-hydroxybenzylidene) benzohydrazide (D0)] that were highly effective in vitro and in vivo against several pathogenic fungi. BHBM and D0 were well tolerated in animals and are highly synergistic or additive to current antifungals. BHBM and D0 significantly affected fungal cell morphology and resulted in the accumulation of intracellular vesicles. Deep-sequencing analysis of drug-resistant mutants revealed that four protein products, encoded by genes APL5, COS111, MKK1, and STE2, which are involved in vesicular transport and cell cycle progression, are targeted by BHBM. IMPORTANCE: Fungal infections are a significant cause of morbidity and mortality worldwide. Current antifungal drugs suffer from various drawbacks, including toxicity, drug resistance, and narrow spectrum of activity. In this study, we have demonstrated that pharmaceutical inhibition of fungal glucosylceramide presents a new opportunity to treat cryptococcosis and various other fungal infections. In addition to being effective against pathogenic fungi, the compounds discovered in this study were well tolerated by animals and additive to current antifungals. These findings suggest that these drugs might pave the way for the development of a new class of antifungals.


Assuntos
Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Compostos de Benzil/isolamento & purificação , Compostos de Benzil/farmacologia , Vias Biossintéticas/efeitos dos fármacos , Fungos/efeitos dos fármacos , Esfingolipídeos/biossíntese , Animais , Antifúngicos/efeitos adversos , Antifúngicos/toxicidade , Compostos de Benzil/efeitos adversos , Compostos de Benzil/toxicidade , Candidíase/tratamento farmacológico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Sinergismo Farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Fungos/citologia , Fungos/metabolismo , Fungos/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Camundongos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Microscopia Eletrônica de Transmissão , Estrutura Molecular , Esfingolipídeos/antagonistas & inibidores , Resultado do Tratamento
5.
Rev. iberoam. micol ; 32(1): 34-39, ene.-mar. 2015. ilus
Artigo em Inglês | IBECS | ID: ibc-132894

RESUMO

Background. Candida guilliermondii has been recognized as an emerging pathogen showing a decreased susceptibility to fluconazole and considerably high echinocandin MICs. Aims. Evaluate the in vitro activity of anidulafungin in comparison to amphotericin B and fluconazole against different isolates of C. guilliermondii, and their efficacy in an immunosuppressed murine model of disseminated infection. Methods. The in vitro susceptibility of four strains against amphotericin B, fluconazole and anidulafungin was performed by using a reference broth microdilution method and time-kill curves. The in vivo efficacy was evaluated by determination of fungal load reduction in kidneys of infected animals receiving deoxycholate AMB at 0,8 mg/kg i.v., liposomal amphotericin B at 10 mg/kg i.v., fluconazole at 50 mg/kg, or anidulafungin at 10 mg/kg. Results. Amphotericin B and anidulafungin showed fungicidal activity, while fluconazole was fungistatic for all the strains. In the murine model, liposomal amphotericin B at 10 mg/kg/day was effective in reducing the tissue burden in kidneys of mice infected with any of the tested strains. However, amphotericin B, anidulafungin and fluconazole were only effective against those strains showing low MIC values. Conclusions. Liposomal amphotericin B showed the higher activity and efficacy against the two strains of C. guilliermondii, in contrast to the poor effect of fluconazole and anidulafungin. Further studies with more isolates of C. guilliermondii representing a wider range of MICs should be carried out to assess whether there is any relationship between MIC values and anidulafungin efficacy (AU)


Antecedentes. Candida guilliermondii es un patógeno emergente, con reducida sensibilidad al fluconazol y a las equinocandinas. Objetivos. Evaluar la actividad in vitro de la anidulafungina, en comparación con la de la anfotericina B y el fluconazol, frente a C. guilliermondii y su eficacia en un modelo animal de infección diseminada. Métodos. La sensibilidad in vitro se valoró mediante microdilución en caldo y curvas de mortalidad. La eficacia in vivo se evaluó mediante la determinación de la carga fúngica en riñón de ratones inmunosuprimidos con infección diseminada por C. guilliermondii tratados con anfotericina B desoxicolato (0.8 mg/kg i.v.), anfotericina B liposomal (10 mg/kg i.v.), fluconazol (50 mg/kg) o anidulafungina (10 mg/kg). Resultados. La anfotericina B y la anidulafungina mostraron actividad fungicida, mientras que el fluconazol fue fungistático frente a todas las cepas. En el modelo murino, la anfotericina B liposomal redujo para todas las cepas la carga fúngica en riñones, mientras que la anfotericina B desoxicolato, la anidulafungina y el fluconazol fueron efectivas solo en aquellos animales infectados con las cepas de menor valor de concentración mínima inhibitoria (CMI). Conclusiones. La anfotericina B liposomal mostró la mayor actividad y eficacia frente a C. guilliermondii, en contraste con el limitado efecto del fluconazol y de la anidulafungina. Se necesitan estudios que incluyan cepas con un rango más amplio de CMI que permitan determinar la relación entre la actividad in vitro y la eficacia de la anidulafungina (AU)


Assuntos
Animais , Masculino , Feminino , Camundongos , Candida , Candida/isolamento & purificação , Candida/metabolismo , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Modelos Animais , Ácido Desoxicólico/uso terapêutico , Resultado do Tratamento , Avaliação de Eficácia-Efetividade de Intervenções , Testes de Sensibilidade Microbiana/métodos , Sensibilidade e Especificidade , Fluconazol/metabolismo , Fluconazol/farmacocinética , Fluconazol/uso terapêutico , Anfotericina B/uso terapêutico
6.
Antimicrob Agents Chemother ; 59(1): 690-2, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25331706

RESUMO

The in vitro and in vivo activity of the inositol acyltransferase inhibitor E1210 was evaluated against echinocandin-resistant Candida albicans. E1210 demonstrated potent in vitro activity, and in mice with invasive candidiasis caused by echinocandin-resistant C. albicans, oral doses of 10 and 40 mg E1210/kg of body weight twice daily significantly improved survival and reduced fungal burden compared to those of controls and mice treated with caspofungin (10 mg/kg/day). These results demonstrate the potential use of E1210 against resistant C. albicans infections.


Assuntos
Aminopiridinas/farmacologia , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candidíase Invasiva/tratamento farmacológico , Isoxazóis/farmacologia , Aminopiridinas/uso terapêutico , Animais , Antifúngicos/uso terapêutico , Caspofungina , Relação Dose-Resposta a Droga , Farmacorresistência Fúngica , Equinocandinas/farmacologia , Equinocandinas/uso terapêutico , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Isoxazóis/uso terapêutico , Lipopeptídeos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana
7.
Rev Iberoam Micol ; 32(1): 34-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-24594291

RESUMO

BACKGROUND: Candida guilliermondii has been recognized as an emerging pathogen showing a decreased susceptibility to fluconazole and considerably high echinocandin MICs. AIMS: Evaluate the in vitro activity of anidulafungin in comparison to amphotericin B and fluconazole against different isolates of C. guilliermondii, and their efficacy in an immunosuppressed murine model of disseminated infection. METHODS: The in vitro susceptibility of four strains against amphotericin B, fluconazole and anidulafungin was performed by using a reference broth microdilution method and time-kill curves. The in vivo efficacy was evaluated by determination of fungal load reduction in kidneys of infected animals receiving deoxycholate AMB at 0,8 mg/kg i.v., liposomal amphotericin B at 10 mg/kg i.v., fluconazole at 50 mg/kg, or anidulafungin at 10 mg/kg. RESULTS: Amphotericin B and anidulafungin showed fungicidal activity, while fluconazole was fungistatic for all the strains. In the murine model, liposomal amphotericin B at 10 mg/kg/day was effective in reducing the tissue burden in kidneys of mice infected with any of the tested strains. However, amphotericin B, anidulafungin and fluconazole were only effective against those strains showing low MIC values. CONCLUSIONS: Liposomal amphotericin B showed the higher activity and efficacy against the two strains of C. guilliermondii, in contrast to the poor effect of fluconazole and anidulafungin. Further studies with more isolates of C. guilliermondii representing a wider range of MICs should be carried out to assess whether there is any relationship between MIC values and anidulafungin efficacy.


Assuntos
Anfotericina B/farmacologia , Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Candidíase Invasiva/tratamento farmacológico , Equinocandinas/farmacologia , Fluconazol/farmacologia , Anidulafungina , Animais , Antifúngicos/uso terapêutico , Candida/isolamento & purificação , Candidíase Invasiva/etiologia , Candidíase Invasiva/microbiologia , Doenças Transmissíveis Emergentes/microbiologia , Avaliação Pré-Clínica de Medicamentos , Rim/microbiologia , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Neutropenia/complicações , Distribuição Aleatória , Especificidade da Espécie
8.
Antimicrob Agents Chemother ; 59(2): 1341-3, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25451054

RESUMO

We evaluated the in vitro and in vivo activities of the investigational arylamidine T-2307 against echinocandin-resistant Candida albicans. T-2307 demonstrated potent in vitro activity, and daily subcutaneous doses between 0.75 and 6 mg/kg of body weight significantly improved survival and reduced fungal burden compared to placebo control and caspofungin (10 mg/kg/day) in mice with invasive candidiasis caused by an echinocandin-resistant strain. Thus, T-2307 may have potential use in the treatment of echinocandin-resistant C. albicans infections.


Assuntos
Amidinas/farmacologia , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida albicans/patogenicidade , Equinocandinas/farmacologia , Equinocandinas/uso terapêutico , Animais , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Farmacorresistência Fúngica , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana
9.
Antimicrob Agents Chemother ; 58(10): 6255-7, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25049245

RESUMO

We evaluated the in vitro killing activity of voriconazole (VRC) and posaconazole (PSC) against two clinical isolates of Candida guilliermondii. The two drugs showed fungistatic activity against both isolates and were effective in reducing kidney fungal burden in a neutropenic murine model of disseminated candidiasis in infected mice. PSC was significantly more effective than VRC against one of the strains. The serum levels of PSC and VRC were above the corresponding MICs for these isolates.


Assuntos
Antifúngicos/farmacologia , Azóis/farmacologia , Candida/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Triazóis/farmacologia , Voriconazol/farmacologia
10.
Antimicrob Agents Chemother ; 58(7): 3646-9, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24733474

RESUMO

It has been argued that the in vitro activity of caspofungin (CSP) is not a good predictor of the outcome of echinocandin treatment in vivo. We evaluated the in vitro activity of CSP and the presence of FKS mutations in the hot spot 1 (HS1) region of the FKS1 and FKS2 genes in 17 Candida glabrata strains with a wide range of MICs. The efficacy of CSP against systemic infections from each of the 17 strains was evaluated in a murine model. No HS1 mutations were found in the eight strains showing MICs for CSP of ≤ 0.5 µg/ml, but they were present in eight of the nine strains with MICs of ≥ 1 µg/ml, i.e., three in the FKS1 gene and five in the FKS2 gene. CSP was effective for treating mice infected with strains with MICs of ≤ 0.5 µg/ml, showed variable efficacy in animals challenged with strains with MICs of 1 µg/ml, and did not work in those with strains with MICs of >1 µg/ml. In addition, mutations, including one reported for the first time, were found outside the HS1 region in the FKS2 gene of six strains with different MICs, but their presence did not influence drug efficacy. The in vitro activity of CSP was compared with that of another echinocandin, anidulafungin, suggesting that the MICs of both drugs, as well as mutations in the HS1 regions of the FKS1 and FKS2 genes, are predictive of outcome.


Assuntos
Antifúngicos/farmacologia , Candida glabrata/efeitos dos fármacos , Candidíase/tratamento farmacológico , Equinocandinas/farmacologia , Proteínas Fúngicas/genética , Glucosiltransferases/genética , Mutação/fisiologia , Animais , Candida glabrata/genética , Candidíase/microbiologia , Caspofungina , Farmacorresistência Fúngica/genética , Rim/microbiologia , Lipopeptídeos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Taxa de Sobrevida
11.
Int J Antimicrob Agents ; 43(2): 161-4, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24360922

RESUMO

The in vitro activities of fluconazole (FLC), amphotericin B (AmB) and caspofungin (CSP) were evaluated against three isolates of Candida lusitaniae using time-kill curves. AmB showed in vitro fungicidal activity, whilst FLC and CSP exerted mainly strain-dependent fungistatic activity. The in vivo efficacies of the three drugs were evaluated in a murine model of disseminated infection. The doses administered were FLC 50 mg/kg/day, AmB 0.8 mg/kg/day and CSP 5 mg/kg/day. All three drugs were able to reduce the fungal burden in the kidneys of infected mice, with AmB showing the highest efficacy, followed by CSP. At least in this model, FLC, AmB and CSP are good candidates for treating invasive infections by C. lusitaniae.


Assuntos
Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Equinocandinas/uso terapêutico , Fluconazol/uso terapêutico , Animais , Candidíase/microbiologia , Caspofungina , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Rim/microbiologia , Lipopeptídeos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Resultado do Tratamento
12.
Diagn Microbiol Infect Dis ; 77(1): 41-5, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23806662

RESUMO

We have evaluated the in vitro activity of caspofungin against 36 wild-type strains of Candida parapsilosis sensu stricto using 3 techniques: broth microdilution, disk diffusion, and the determination of minimal fungicidal concentration (MFC). The first 2 methods showed a good in vitro activity of caspofungin, but the MFCs were ≥2 dilutions above their corresponding MICs. In a murine model of disseminated infection, we evaluated the efficacy of caspofungin at 5 mg/kg against 8 strains of C. parapsilosis representing different degrees of in vitro susceptibility (0.12-1 µg/mL). All the isolates responded to treatment and (1→3)-ß-D-glucan levels were reduced in all the cases; however, the study revealed differences among isolates, since caspofungin reduced the tissue burden of mice infected with isolates with MICs ≤0.5 µg/mL but was less effective against those with MICs of 1 µg/mL.


Assuntos
Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Equinocandinas/farmacologia , Equinocandinas/uso terapêutico , Animais , Candidíase/microbiologia , Caspofungina , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Lipopeptídeos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Proteoglicanas , Resultado do Tratamento , beta-Glucanas/sangue
13.
Antimicrob Agents Chemother ; 57(3): 1532-4, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23295929

RESUMO

We evaluated the efficacy of voriconazole against nine strains of Aspergillus terreus with different MICs (0.12 to 4 µg/ml) by using a murine model. Markers of efficacy included survival, tissue burden, galactomannan antigenemia, and drug serum levels. Voriconazole was especially effective in prolonging survival and reducing the fungal load in infections by strains that showed MICs that were less than or equal to the epidemiological cutoff value (1 µg/ml). In vitro data might be useful for predicting the outcome of A. terreus infections.


Assuntos
Antifúngicos/farmacologia , Aspergilose/tratamento farmacológico , Aspergillus/efeitos dos fármacos , Pirimidinas/farmacologia , Triazóis/farmacologia , Anfotericina B/farmacologia , Animais , Aspergilose/imunologia , Aspergilose/microbiologia , Aspergilose/mortalidade , Aspergillus/crescimento & desenvolvimento , Aspergillus/isolamento & purificação , Farmacorresistência Fúngica/efeitos dos fármacos , Galactose/análogos & derivados , Masculino , Mananas/antagonistas & inibidores , Mananas/imunologia , Camundongos , Testes de Sensibilidade Microbiana , Prognóstico , Análise de Sobrevida , Voriconazol
15.
Future Med Chem ; 1(2): 379-89, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-21425974

RESUMO

BACKGROUND: The Streptomyces-derived nikkomycins are a unique class of peptidyl nucleoside natural products, with potent antifungal activity against a variety of pathogenic fungi. RESULTS: In continuation of our structure-activity relationship studies on the nikkomycins, this paper describes the strategic design, synthesis and biological evaluation of a 'doubly modified' generation of nikkomycin analogs. The structural modifications included a ring-expanded carbohydrate core and a simplified peptidyl side chain. Biological screening of these novel analogs against clinical isolates of various human pathogenic fungi indicated that the described modifications of the structural features of nikkomycin could be a potentially beneficial strategy towards optimizing the antifungal potency of this class of peptidyl nucleoside antibiotics. CONCLUSION: Continued investigation of the pyranosyl nikkomycin analogs is warranted to fully explore and optimize the structural features of this novel lead for the desired development of a new class of therapeutically useful antifungal drugs.


Assuntos
Aminoglicosídeos/química , Antifúngicos/síntese química , Aminoglicosídeos/síntese química , Aminoglicosídeos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Testes de Sensibilidade Microbiana , Nucleosídeos/química , Peptídeos/química , Streptomyces/química , Relação Estrutura-Atividade
16.
J Antimicrob Chemother ; 62(5): 1094-100, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18658194

RESUMO

BACKGROUND: Aminocandin is an investigational echinocandin with excellent activity against Candida species, including Candida albicans and Candida tropicalis. However, few data are available for this agent versus Candida glabrata. We compared the in vitro potency and in vivo efficacy of aminocandin and caspofungin against clinical isolates of C. glabrata including those with reduced caspofungin susceptibility (MIC > 2 mg/L). METHODS: In vitro activity was assessed using microdilution broth susceptibility testing. Three isolates, one with a low and two with elevated caspofungin MICs, were chosen and mice were infected with C. glabrata followed by a single dose of aminocandin or caspofungin (0.5-100 mg/kg), or daily doses of caspofungin (0.07-14.3 mg/kg) begun 1 day after inoculation. Reduction in fungal burden, assessed in kidney tissue on day 8 post-inoculation, was the marker of antifungal response. RESULTS: Aminocandin was more potent than caspofungin against each isolate with reduced caspofungin susceptibility. Mice infected with the caspofungin-susceptible isolate had significant decreases in tissue burden with low doses of either drug. Higher single doses of aminocandin (> or = 10 mg/kg) were required to reduce fungal burden against the two isolates with elevated caspofungin MICs. Single dose administration of caspofungin was ineffective against one of these isolates, and higher daily doses were required to reduce fungal burden. CONCLUSIONS: These studies suggest that aminocandin has the potential for extended interval dosing in the treatment of C. glabrata infections caused by susceptible isolates. However, higher doses may be required against isolates with reduced caspofungin susceptibility.


Assuntos
Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida glabrata/efeitos dos fármacos , Candidíase/tratamento farmacológico , Farmacorresistência Fúngica , Equinocandinas/farmacologia , Equinocandinas/uso terapêutico , Lipopeptídeos/farmacologia , Lipopeptídeos/uso terapêutico , Animais , Antifúngicos/administração & dosagem , Caspofungina , Contagem de Colônia Microbiana , Equinocandinas/administração & dosagem , Rim/microbiologia , Lipopeptídeos/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana
17.
Antimicrob Agents Chemother ; 51(7): 2587-90, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17452481

RESUMO

We evaluated the in vitro susceptibilities of 217 zygomycetes to amphotericin B, ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, caspofungin, and flucytosine. The significant in vitro activity of posaconazole against several species appears to support its reported clinical efficacy. Decreased susceptibility to amphotericin B was noted with Cunninghamella bertholletiae.


Assuntos
Antifúngicos/uso terapêutico , Mucormicose/tratamento farmacológico , Anfotericina B/uso terapêutico , Caspofungina , Equinocandinas , Fluconazol/uso terapêutico , Flucitosina/uso terapêutico , Humanos , Técnicas In Vitro , Itraconazol/uso terapêutico , Cetoconazol/uso terapêutico , Lipopeptídeos , Testes de Sensibilidade Microbiana , Peptídeos Cíclicos/uso terapêutico , Pirimidinas/uso terapêutico , Triazóis/uso terapêutico , Voriconazol
19.
Antimicrob Agents Chemother ; 49(11): 4751-3, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16251321

RESUMO

Antagonistic effects of combination therapy using amphotericin B (AmB) with agents which block ergosterol synthesis are a concern. Terbinafine was evaluated with AmB to assess antagonism or synergy in a rabbit model of invasive aspergillosis. Terbinafine had relatively little activity but did not demonstrate antagonism against AmB in our model.


Assuntos
Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Aspergilose/tratamento farmacológico , Naftalenos/administração & dosagem , Animais , Aspergillus fumigatus/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Testes de Sensibilidade Microbiana , Coelhos , Terbinafina
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