In vitro and in vivo antifungal activities of T-2307, a novel arylamidine, against Cryptococcus gattii: an emerging fungal pathogen

  • J Antimicrob Chemother. 2017 Jun 1;72(6):1709-1713. doi: 10.1093/jac/dkx020.
Hiroshi Nishikawa  1 ,  Yoshiko Fukuda  1 ,  Junichi Mitsuyama  1 ,  Masato Tashiro  2 ,  Akitaka Tanaka  3 ,  Takahiro Takazono  2 ,  Tomomi Saijo  4 ,  Kazuko Yamamoto  3  4 ,  Shigeki Nakamura  5 ,  Yoshifumi Imamura  4 ,  Taiga Miyazaki  2  4 ,  Hiroshi Kakeya  6 ,  Yoshihiro Yamamoto  7 ,  Katsunori Yanagihara  8 ,  Hiroshi Mukae  4  9 ,  Shigeru Kohno  4  9 ,  Koichi Izumikawa  2
Affiliations
  • 1. Research Laboratories, Toyama Chemical Co., Ltd, 2-4-1 Shimookui, Toyama, Japan.
  • 2. Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
  • 3. Infection Control and Education Center, Nagasaki University Hospital, Nagasaki, Japan.
  • 4. Second Department of Internal Medicine, Nagasaki University Hospital, Nagasaki, Japan.
  • 5. Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan.
  • 6. Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Osaka, Japan.
  • 7. Department of Clinical Infectious Diseases, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan.
  • 8. Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
  • 9. Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
PMID: 28201509 DOI: 10.1093/jac/dkx020
Abstract

Objectives: 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 .

Methods: 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.

Results: 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.

Conclusions: 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.

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