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

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.

• Authors: Hiroshi Nishikawa, Yoshiko Fukuda, Junichi Mitsuyama, Masato Tashiro, Akitaka Tanaka, Takahiro Takazono, Tomomi Saijo, Kazuko Yamamoto, Shigeki Nakamura, Yoshifumi Imamura, Taiga Miyazaki, Hiroshi Kakeya, Yoshihiro Yamamoto, Katsunori Yanagihara, Hiroshi Mukae, Shigeru Kohno, Koichi Izumikawa
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 72 Issue 6 Pg. 1709-1713 (06 01 2017) ISSN: 1460-2091 [Electronic] England
• PMID: 28201509 (Publication Type: Journal Article)
• Copyright: © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Amidines
• Antifungal Agents
• T-2307
• Amphotericin B
• Fluconazole
• Voriconazole

Topics

• Amidines (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Amphotericin B (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Animals
• Antifungal Agents (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Brain (microbiology)
• Cryptococcosis (drug therapy, microbiology)
• Cryptococcus gattii (drug effects, pathogenicity)
• Cryptococcus neoformans (drug effects)
• Disease Models, Animal
• Drug Discovery
• Drug Resistance, Fungal
• Fluconazole (pharmacology, therapeutic use)
• Humans
• Lung (microbiology)
• Lung Diseases, Fungal (drug therapy, microbiology)
• Mice
• Microbial Sensitivity Tests
• Voriconazole (pharmacology, therapeutic use)