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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(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
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(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
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
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