Nishikawa Hiroshi, Fukuda Yoshiko, Mitsuyama Junichi, Tashiro Masato, Tanaka Akitaka, Takazono Takahiro, Saijo Tomomi, Yamamoto Kazuko, Nakamura Shigeki, Imamura Yoshifumi, Miyazaki Taiga, Kakeya Hiroshi, Yamamoto Yoshihiro, Yanagihara Katsunori, Mukae Hiroshi, Kohno Shigeru, Izumikawa Koichi
Research Laboratories, Toyama Chemical Co., Ltd, 2-4-1 Shimookui, Toyama, Japan.
Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
J Antimicrob Chemother. 2017 Jun 1;72(6):1709-1713. doi: 10.1093/jac/dkx020.
T-2307, a novel arylamidine, exhibits potent broad-spectrum activities against the majority of fungal pathogens. In this study, the antifungal activity of T-2307 against Cryptococcus gattii was evaluated in comparison with those of amphotericin B, fluconazole and voriconazole in vitro and in vivo .
The MICs for 15 clinical isolates were determined according to CLSI guidelines and time-kill studies were performed using C. gattii YF2784. In a murine model for intranasal pulmonary infection caused by C. gattii YF2784, the test compounds were administered once daily for 7 days from 2 h or 14 days post-infection. The viable counts in the lungs and brain were determined at 21 days post-infection.
The MIC range, MIC 50 , MIC 90 and geometric mean MIC of T-2307 were 0.0078-0.0625, 0.0313, 0.0625 and 0.0394 mg/L, respectively. The MIC of T-2307 was significantly lower than those of fluconazole, voriconazole and amphotericin B. T-2307 showed concentration-dependent fungicidal activity at 4 times the MIC or higher. Administration of T-2307 at 2 mg/kg/day, amphotericin B at 1 mg/kg/day and fluconazole at 160 mg/kg/day from 2 h post-infection significantly reduced viable counts in the lungs and brain. However, when the administration was started 14 days post-infection, only T-2307 significantly reduced the viable counts in both the lungs and the brain at 1 mg/kg/day.
T-2307 shows excellent in vitro and in vivo antifungal activities against C. gattii and would be a promising new candidate for the treatment of cryptococcosis.
新型芳脒T-2307对大多数真菌病原体具有强大的广谱活性。在本研究中，在体外和体内评估了T-2307对加氏隐球菌的抗真菌活性，并与两性霉素B、氟康唑和伏立康唑进行了比较。
根据CLSI指南测定15株临床分离株的最低抑菌浓度（MIC），并使用加氏隐球菌YF2784进行时间杀菌研究。在由加氏隐球菌YF2784引起的鼻内肺部感染小鼠模型中，从感染后2小时或14天开始，每天给药一次，持续7天。在感染后21天测定肺和脑中的活菌数。
T-2307的MIC范围、MIC50、MIC90和几何平均MIC分别为0.0078-0.0625、0.0313、0.0625和0.0394mg/L。T-2307的MIC显著低于氟康唑、伏立康唑和两性霉素B。T-2307在4倍MIC或更高浓度时表现出浓度依赖性杀菌活性。从感染后2小时开始，以2mg/kg/天的剂量给予T-2307、1mg/kg/天的剂量给予两性霉素B和160mg/kg/天的剂量给予氟康唑，可显著降低肺和脑中的活菌数。然而，当在感染后14天开始给药时，只有T-2307以1mg/kg/天的剂量显著降低了肺和脑中的活菌数。
T-2307对加氏隐球菌显示出优异的体外和体内抗真菌活性，有望成为治疗隐球菌病的新候选药物。
