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

Abstract

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.

Mitochondrial Complex I Core Protein Regulates cAMP Signaling via Phosphodiesterase Pde2 and NAD Homeostasis in Candida albicans

“…A strategy for the development of novel antifungals has been to identify new antifungals that act against fungal-or even Candidaspecific targets (Gintjee et al, 2020;Li et al, 2020). The current antifungal pipeline on specific metabolic targets includes olorofim (nucleic acid synthesis) (Oliver et al, 2016), fosmanogepix (MGX) [glycosylphosphatidylinositol (GPI) synthesis] (Alkhazraji et al, 2019), and arylamidine T2307 (mitochondria) (Yamashita et al, 2019).…”

Review of T-2307, an Investigational Agent That Causes Collapse of Fungal Mitochondrial Membrane Potential

“…A previous publication stated that this agent has successfully completed phase I studies without adverse effects [ 23 ], but these data are not currently available. In in vitro studies, as previously discussed, T-2307 has demonstrated a greater selectivity for the inhibition of yeast mitochondrial function when compared to that observed against rat and bovine mitochondria [ 13 , 19 ]. In addition, T-2307 has been reported to be well-tolerated in immunocompetent and neutropenic murine models of invasive fungal infections at doses of up to 6 mg/kg/day [ 12 , 14 , 20 , 21 , 22 , 23 ].…”

“…To further assess the mechanism of action of T-2307 on the mitochondrial function, Yamashita et al measured oxygen consumption in whole yeast cells [ 19 ]. Respiration was inhibited by T-2307 in a dose-dependent fashion, while respiration was not stimulated at any tested concentration (up to 1000 µM).…”

Current Antimycotics, New Prospects, and Future Approaches to Antifungal Therapy

“…Moreover, although first discovered in the 1970s, the chitin inhibitor Nikkomycin Z is currently undergoing clinical trials against coccidioidomycosis [47]. Other notable molecules under development include Aureobasidin A, a cyclic peptide that inhibits fungal sphingolipid biosynthesis with potent broad spectrum antifungal activity [48]; and T-2307, from Toyama Corporation, an investigational arylamidine, which is active against yeast and moulds [49].…”