T-2307, a novel arylamidine, is transported into<i>Candida albicans</i>by a high-affinity spermine and spermidine carrier regulated by Agp2

Nishikawa, Hiroshi; Sakagami, Toru; Yamada, Eichi; Fukuda, Yoshiko; Hayakawa, Hiroyoshi; Nomura, Nobuhiko; Mitsuyama, Junichi; Miyazaki, Taiga; Mukae, Hiroshi; Kohno, Shigeru

doi:10.1093/jac/dkw095

Cited by 26 publications

(15 citation statements)

References 41 publications

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“…It has interesting and unusual mechanisms for selectivity and activity. First, the compound is selectively transported and accumulates in fungal cells through a specific polyamine transporter 68 . Once inside the yeast cell, it specifically inhibits the mitochondrial membrane potential, and this has profound fungicidal activity, as the fungal strains that cause human disease are primarily respiratory fungi 69 .…”

Section: New Agents In Developmentmentioning

confidence: 99%

The antifungal pipeline: a reality check

Perfect

2017

Nat Rev Drug Discov

627

575

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Invasive fungal infections continue to appear in record numbers as the immunocompromised population of the world increases, owing partially to the increased number of individuals who are infected with HIV and partially to the successful treatment of serious underlying diseases. The effectiveness of current antifungal therapies — polyenes, flucytosine, azoles and echinocandins (as monotherapies or in combinations for prophylaxis, or as empiric, pre-emptive or specific therapies) — in the management of these infections has plateaued. Although these drugs are clinically useful, they have several limitations, such as off-target toxicity, and drug-resistant fungi are now emerging. New antifungals are therefore needed. In this Review, I discuss the robust and dynamic antifungal pipeline, including results from preclinical academic efforts through to pharmaceutical industry products, and describe the targets, strategies, compounds and potential outcomes.

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Section: New Agents In Developmentmentioning

confidence: 99%

The antifungal pipeline: a reality check

Perfect

2017

Nat Rev Drug Discov

627

575

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“…The hypothesized mechanism of action of T-2307. T-2307 is concentrated in yeast cells by a specific transporter (12, 13). T-2307 inhibits mitochondrial respiratory chain complexes, which leads to a decrease in intracellular ATP levels.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism of action of T-2307 has been investigated in several studies (12–14). T-2307 is incorporated into yeast cells by a specific polyamine transporter related to the uptake of spermine and spermidine, and its concentration reportedly increases >3,000-fold in C.…”

Section: Introductionmentioning

confidence: 99%

“…T-2307 is incorporated into yeast cells by a specific polyamine transporter related to the uptake of spermine and spermidine, and its concentration reportedly increases >3,000-fold in C. albicans from the extracellular medium (12, 13). Once inside the cytosol, T-2307 reaches mitochondria and disrupts the mitochondrial membrane potential (MMP), resulting in mitochondrial dysfunction (14).…”

Section: Introductionmentioning

confidence: 99%

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The Novel Arylamidine T-2307 Selectively Disrupts Yeast Mitochondrial Function by Inhibiting Respiratory Chain Complexes

Yamashita

Miyazaki

Fukuda

et al. 2019

Antimicrob Agents Chemother

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The novel arylamidine T-2307 exhibits broad-spectrum in vitro and in vivo antifungal activities against clinically significant pathogens. Previous studies have shown that T-2307 accumulates in yeast cells via a specific polyamine transporter and disrupts yeast mitochondrial membrane potential. Further, it has little effect on rat liver mitochondrial function. The mechanism by which T-2307 disrupts yeast mitochondrial function is poorly understood, and its elucidation may provide important information for developing novel antifungal agents. This study aimed to determine how T-2307 promotes yeast mitochondrial dysfunction and to investigate the selectivity of this mechanism between fungi and mammals. T-2307 inhibited the respiration of yeast whole cells and isolated yeast mitochondria in a dose-dependent manner. The similarity of the effects of T-2307 and respiratory chain inhibitors on mitochondrial respiration prompted us to investigate the effect of T-2307 on mitochondrial respiratory chain complexes. T-2307 particularly inhibited respiratory chain complexes III and IV not only in Saccharomyces cerevisiae but also in Candida albicans, indicating that T-2307 acts against pathogenic fungi in a manner similar to that of yeast. Conversely, T-2307 showed little effect on bovine respiratory chain complexes. Additionally, we demonstrated that the inhibition of respiratory chain complexes by T-2307 resulted in a decrease in the intracellular ATP levels in yeast cells. These results indicate that inhibition of respiratory chain complexes III and IV is a key factor for selective disruption of yeast mitochondrial function and antifungal activity.

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“…Аллиламин Т-2307 (компания Tokuyama Corporation) обладает широкой противогрибковой активностью широкого спектра действия против Candida spp., Cryptococcus spp. и Aspergillus spp., с низкими минимальными ингибирующими концентрациями для дрожжей и плесневых грибов [27,28].…”

Section: несколько новых соединений -(N'-(3-бром-4гидроксибензилиден)unclassified

Search for new antimycotic agents: main trends and problems

Новикова¹

2020

Kursk Scientific and Practical Bulletin “Man and His Health”

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

Cited by 26 publications

References 41 publications

The antifungal pipeline: a reality check

The antifungal pipeline: a reality check

The Novel Arylamidine T-2307 Selectively Disrupts Yeast Mitochondrial Function by Inhibiting Respiratory Chain Complexes

Search for new antimycotic agents: main trends and problems

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