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

Nathan P Wiederhold

doi:10.3390/jof7020130

Abstract

Invasive infections caused by Candida that are resistant to clinically available antifungals are of increasing concern. Increasing rates of fluconazole resistance in non-albicans Candida species have been documented in multiple countries on several continents. This situation has been further exacerbated over the last several years by Candida auris, as isolates of this emerging pathogen that are often resistant to multiple antifungals. T-2307 is an aromatic diamidine currently in development for the treatment of invasive fungal infections. This agent has been shown to selectively cause the collapse of the mitochondrial membrane potential in yeasts when compared to mammalian cells. In vitro activity has been demonstrated against Candida species, including C. albicans, C. glabrata, and C. auris strains, which are resistant to azole and echinocandin antifungals. Activity has also been reported against Cryptococcus species, and this has translated into in vivo efficacy in experimental models of invasive candidiasis and cryptococcosis. However, little is known regarding the clinical efficacy and safety of this agent, as published data from studies involving humans are not currently available.

Highlights

Infections caused by fungi are of increasing clinical concern
The disconnect between the T-2307 concentration required to cause the collapse of the mitochondrial membrane potential and that needed to inhibit the growth of the organism (MIC) was postulated to be due to the intracellular accumulation of T-2307, as others have reported that this agent concentrates approximately 5000-fold within C. albicans cells from an extracellular medium via transporter mediated systems [16]
Against mitochondria isolated from a bovine heart, the T-2307 IC50 values were >3000 μM against all mitochondrial respiratory chain enzyme complexes. These results further demonstrate the selectivity of T-2307 against the yeast mitochondrial function

Summary

Introduction

Infections caused by fungi are of increasing clinical concern. These include invasive diseases caused by strains of Candida species that are resistant to clinically available antifungals. The utility of clinically available antifungals is often limited by drug–drug interactions and toxicities, which can occur frequently in patients at a high risk of invasive fungal infections who are often receiving multiple concomitant medications [8,9,10,11]. T-2307 (4-{3-[1-(3-{4-{amino(imino)methyl]phenoxy}propyl)piperidin-4-yl]propoxy} benzmide) is an investigational agent currently under evaluation and in development for the treatment of invasive fungal infections, including those caused by Candida species that are resistant to clinically approved antifungals, including azole- and echinocandin-resistant strains. Candida species, including azole- and echinocandin-resistant isolates, Cryptococcus neoformans & C. gattii.

Structure and Mechanism of Action

In Vitro Spectrum of Activity

In Vivo Effectiveness

Findings

Conclusions