Uptake of T-2307, a novel arylamidine, in Candida albicans

Nishikawa, Hiroshi; Yamada, Eichi; Shibata, Tatsuya; Uchihashi, Shinsuke; Fan, Haitian; Hayakawa, Hiroyoshi; Nomura, Nobuhiko; Mitsuyama, Junichi

doi:10.1093/jac/dkq177

Cited by 37 publications

(32 citation statements)

References 28 publications

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“…Since the affinity of pentamidine for these transporters is low, the difference in in vitro antifungal activity between T-2307 and pentamidine may be due to the difference in the uptake rate. We also confirmed that T-2307 is incorporated by C. albicans with approximately 130 times higher concentration than that by mammalian cells (19). T-2307 showed marked selectivity for C. albicans over mammalian cells regarding in vitro growth inhibition (data not shown).…”

Section: Resultssupporting

confidence: 71%

“…We considered that this disconnect may be because T-2307 is actively accumulated by cells. It has been reported that T-2307 is concentrated approximately 5,000-fold from the extracellular medium by C. albicans cells (19). In our preliminary experiments, T-2307 at 10 M significantly collapsed the membrane potential of mitochondria isolated from C. albicans.…”

Section: Resultsmentioning

confidence: 43%

“…We previously confirmed that T-2307 was actively incorporated into C. albicans through two specific transporters (19). Since the affinity of pentamidine for these transporters is low, the difference in in vitro antifungal activity between T-2307 and pentamidine may be due to the difference in the uptake rate.…”

Section: Resultsmentioning

confidence: 58%

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T-2307 Causes Collapse of Mitochondrial Membrane Potential in Yeast

Shibata

Takahashi

Yamada

et al. 2012

Antimicrob Agents Chemother

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T-2307, an arylamidine compound, has been previously reported to have broad-spectrum in vitro and in vivo antifungal activities against clinically significant pathogens, including Candida species, Cryptococcus neoformans, and Aspergillus species, and is now undergoing clinical trials. Here we investigated the mechanism of action of T-2307 using yeast cells and mitochondria isolated from yeast and rat liver. Nonfermentative growth of Candida albicans and Saccharomyces cerevisiae in glycerol medium, in which yeasts relied on mitochondrial respiratory function, was inhibited at 0.001 to 0.002 g/ml (0.002 to 0.004 M) of T-2307. However, fermentative growth in dextrose medium was not inhibited by T-2307. Microscopic examination using Mitotracker fluorescent dye, a cell-permeant mitochondrion-specific probe, demonstrated that T-2307 impaired the mitochondrial function of C. albicans and S. cerevisiae at concentrations near the MIC in glycerol medium. T-2307 collapsed the mitochondrial membrane potential in mitochondria isolated from S. cerevisiae at 20 M. On the other hand, in isolated rat liver mitochondria, T-2307 did not have any effect on the mitochondrial membrane potential at 10 mM. Moreover, T-2307 had little inhibitory and stimulatory effect on mitochondrial respiration in rat liver mitochondria. In conclusion, T-2307 selectively disrupted yeast mitochondrial function, and it was also demonstrated that the fungal mitochondrion is an attractive antifungal target.

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Section: Resultssupporting

confidence: 71%

Section: Resultsmentioning

confidence: 43%

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T-2307 Causes Collapse of Mitochondrial Membrane Potential in Yeast

Shibata

Takahashi

Yamada

et al. 2012

Antimicrob Agents Chemother

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“…7 -9 In our previous study, we characterized the uptake of T-2307 in C. albicans. 10 T-2307 was concentrated into C. albicans cells from the extracellular medium at .3000-fold above the extracellular concentration. The accumulation was approximately two orders of magnitude greater than that achieved with rat hepatocytes.…”

Section: Introductionmentioning

confidence: 99%

T-2307, a novel arylamidine, is transported intoCandida albicansby a high-affinity spermine and spermidine carrier regulated by Agp2

Nishikawa¹,

Sakagami

Yamada

et al. 2016

J. Antimicrob. Chemother.

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“…We had previously reported that T-2307, a novel arylamidine, exhibits broad-spectrum in vitro and in vivo antifungal activity against clinically significant pathogens (7,8,16). The analogous arylamidine derivatives, such as pentamidine and DB75, exhibit antiprotozoan activities against Plasmodium, Trypanosoma, and Leishmania (2,3,14).…”

mentioning

confidence: 99%

In Vitro and In Vivo Antimalarial Activities of T-2307, a Novel Arylamidine

Kimura

Nishikawa

Nomura

et al. 2012

Antimicrob Agents Chemother

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bT-2307, a novel arylamidine, has been shown to exhibit broad-spectrum antifungal activities against clinically significant pathogens. Here, we evaluated the in vitro and in vivo antimalarial activity of T-2307. The 50% inhibitory concentrations (IC 50 s) of T-2307 against Plasmodium falciparum FCR-3 and K-1 strains were 0.47 and 0.17 M, respectively. T-2307 at 2.5 to 10 mg/kg of body weight/day exhibited activity against blood stage and liver stage parasites in rodent malaria models. In conclusion, T-2307 exhibited in vitro and in vivo antimalarial activity. M alaria, caused by protozoan parasites of the genus Plasmodium, is one of the world's leading killer infectious diseases. There are an estimated 200 to 300 million new cases of the disease each year worldwide, and 0.8 to 1 million deaths (5, 15). Many of these deaths occur in children and are the result of severe and cerebral malaria caused by Plasmodium falciparum, the most pathogenic of the four species that infect humans (5).In the absence of a vaccine for malaria and in view of widespread resistance of the parasites to antimalarial drugs in current use, new agents are urgently needed to combat malaria (4).We had previously reported that T-2307, a novel arylamidine, exhibits broad-spectrum in vitro and in vivo antifungal activity against clinically significant pathogens (7, 8, 16). The analogous arylamidine derivatives, such as pentamidine and DB75, exhibit antiprotozoan activities against Plasmodium, Trypanosoma, and Leishmania (2,3,14). Accordingly, T-2307, similar to pentamidine and DB75, is expected to exhibit antiprotozoan activity. In the present study, we investigated the in vitro and in vivo antimalarial activity of T-2307.The in vitro antimalarial activity of T-2307 against P. falciparum was examined. Parasite cultures were maintained in human erythrocytes suspended at 5% hematocrit in RPMI 1640 containing 0.5% AlbuMAX I solution and 5.95 g of HEPES, 2 g of NaHCO 3 , 0.5 g of L-glutamine, and 50 mg of hypoxanthine per liter. After the parasites had been synchronized to the ring stage by sorbitol lysis (6), T-2307 and reference agents were added to the synchronized parasite culture (ring stage, Ͼ90%, and parasitemia, 0.5%) in a 96-well plate. The plate was incubated for one intraerythrocytic life cycle (FCR-3, 40 h, and K-1, 48 h) at 37°C under a gas mixture of 5% O 2 and 5% CO 2 . In order to assess parasite growth, lysis buffer containing 0.02% SYBR green I was added to the parasite culture, and after incubation for 1 h, fluorescence was measured at excitation and emission wavelengths of 485 and 535 nm, respectively (12). The 50% inhibitory concentrations (IC 50 s) of T-2307 and the reference agents against the chloroquine-sensitive P. falciparum FCR-3 strain and the chloroquine-resistant P. falciparum K-1 strain are shown in Table 1. The IC 50 s of T-2307 against FCR-3 and K-1 strains were 0.47 and 0.17 M, respectively, indicating that T-2307 exhibited no cross-resistance against chloroquine.The stage-specific activities of T-2307 and pentami...

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Uptake of T-2307, a novel arylamidine, in Candida albicans

Abstract: The considerably higher concentrations of T-2307 were selectively accumulated in C. albicans via transporter-mediated systems, as compared with the concentrations in rat hepatocytes. This transporter-mediated uptake of T-2307 contributes to its potent anticandidal activity.

Cited by 37 publications

References 28 publications

T-2307 Causes Collapse of Mitochondrial Membrane Potential in Yeast

T-2307 Causes Collapse of Mitochondrial Membrane Potential in Yeast

T-2307, a novel arylamidine, is transported intoCandida albicansby a high-affinity spermine and spermidine carrier regulated by Agp2

In Vitro and In Vivo Antimalarial Activities of T-2307, a Novel Arylamidine

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