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 TratamentoRESUMO
The arginase (ARG)-encoding gene (arg) of Coccidioides immitis, a human fungal pathogen, was cloned and sequenced. Both the genomic and cDNA sequences are provided. The transcription start point and poly(A) sites were confirmed. The arg gene, which was located on chromosome II of C. immitis by Southern hybridization, is a single-copy gene with two introns and a 966-bp ORF which translates a 322-aa protein of 35.1 kDa. The deduced ARG protein showed 44% identity and 68% similarity to the Saccharomyces cerevisiae ARG.