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

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Review of T-2307, an Investigational Agent That Causes Collapse of Fungal Mitochondrial Membrane Potential Journal of Fungi Review Review of T-2307, an Investigational Agent That Causes Collapse of Fungal Mitochondrial Membrane Potential Nathan P. Wiederhold Fungus Testing Laboratory,Department of Pathology and Laboratory Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA; [email protected] 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. Keywords: T-2307; aromatic diamidine; in vitro susceptibility; mitochondrial membrane; mitochondrial membrane potential; Candida; Cryptococcus Citation: Wiederhold, N.P. Review of T-2307, an Investigational Agent That Causes Collapse of Fungal Mitochondrial 1. Introduction Membrane Potential. J. Fungi 2021, 7, 130. https://doi.org/10.3390/ Infections caused by fungi are of increasing clinical concern. These include invasive jof7020130 diseases caused by strains of Candida species that are resistant to clinically available an- tifungals. As highlighted by the World Health Organization global surveillance report Academic Editor: Richard Calderone on antimicrobial resistance, resistance in non-albicans Candida species to fluconazole has been reported at rates of 30% or higher in multiple countries on several continents [1]. At Received: 20 January 2021 some centers in the United States, increased rates of nonsusceptibility to the echinocandins Accepted: 8 February 2021 have also been reported in C. glabrata [2,3]. Interestingly, some studies have also noted Published: 11 February 2021 coresistance to both the echinocandins and the azoles in C. glabrata isolates [3,4]. Recently, the problem of antifungal resistance has been highlighted by the emergence of Candida Publisher’s Note: MDPI stays neutral auris, as many strains of this clinically significant pathogen are multidrug-resistant [5], and with regard to jurisdictional claims in pan-antifungal resistance has also been reported [6,7]. In addition, the utility of clinically published maps and institutional affil- available antifungals is often limited by drug–drug interactions and toxicities, which can iations. occur frequently in patients at a high risk of invasive fungal infections who are often receiving multiple concomitant medications [8–11]. Thus, there is a true need for the development of new antifungals. T-2307 (4-{3-[1-(3-{4-{amino(imino)methyl]phenoxy}propyl)piperidin-4-yl]propoxy} Copyright: © 2021 by the author. benzmide) is an investigational agent currently under evaluation and in development for Licensee MDPI, Basel, Switzerland. the treatment of invasive fungal infections, including those caused by Candida species that This article is an open access article are resistant to clinically approved antifungals, including azole- and echinocandin-resistant distributed under the terms and strains. The initial preclinical and early-stage clinical development of T-2307 has been conditions of the Creative Commons conducted by FUJIFILM Toyama Chemical Co., Ltd., (Tokyo, Japan), which has recently Attribution (CC BY) license (https:// assigned the rights for developing and marketing outside of Japan to Appili Therapeutics creativecommons.org/licenses/by/ (Halifax, NS, Canada; ATI-2307) (http://fftc.fujifilm.co.jp/en/news/news191121e.html, 4.0/). J. Fungi 2021, 7, 130. https://doi.org/10.3390/jof7020130 https://www.mdpi.com/journal/jof J. Fungi 2021, 7, 130 2 of 8 accessed on 15 January, 2021). This review discusses the mechanism of action of T-2307, its spectrum of activity against various fungi, and what is known about its effectiveness in experimental models of invasive fungal infections. Key features of T-2307 are shown in Table1. Table 1. Key features of T-2307. Causes the collapse of the mitochondrial membrane potential by targeting respiratory Mechanism of Action chain enzymatic complexes III and IV in the inner mitochondrial membrane of yeasts. Candida species, including azole- and echinocandin-resistant isolates, Cryptococcus neoformans & C. gattii. Spectrum of Activity Variable activity against Aspergillus species. Limited in vitro data against fungi suggests limited to no activity against Fusarium, Scedosporium, and the Mucorales. Efficacy in murine models of invasive candidiasis caused by C. albicans, C. glabrata, and C. auris; reductions in the ocular fungal burden caused by C. albicans. In vivo activity Efficacy in murine models of systemic aspergillosis due to Aspergillus fumigatus and cryptococcosis caused by C. neoformans and C. gattii. Pharmacokinetic and clinical data Not currently available in the literature. 2. Structure and Mechanism of Action Structurally, T-2307 is an aromatic diamidine, similar to pentamidine and furamidine (DB75) (Figure1)[ 12]. Pentamidine can be used to treat pneumocystis, leishmaniais, and trypanosomiasis, and it is known that pentamidine and furamidine cause the collapse of the mitochondrial membrane potential within Saccharomyces cerevisiae [13–15]. A similar mechanism of action was suspected for T-2307 when it was observed that the degree of its activity against Candida glabrata was strongly influenced by the type and concentration of the carbon source in the growth medium. The trailing effect (i.e., incomplete inhibition of growth at concentrations above the minimum inhibitory concentration [MIC]) was reduced at lower glucose concentrations and was absent when the nonfermentative carbon source glycerol was used [14]. Similarly, S. cerevisiae cells grown in medium containing glycerol were also more sensitive to the effects of pentamidine and furamidine when compared to when they were grown in the presence of glucose. Similar results have also been reported for both T-2307 and pentamidine against C. albicans and S. cerevisiae when growth inhibition J. Fungi 2021, 7, x FOR PEER REVIEW was compared between media containing dextrose and glycerol [13]. Interestingly,3 of 9 both the fermentative (in the presence of dextrose) and nonfermentative (in the presence of glycerol) growth of Cryptococcus neoformans was similarly inhibited by T-2307. (A) (B) Figure 1. ChemicalFigure structures 1. Chemical of th structurese aromatic of diamidines the aromatic (A) diamidinesT-2307 and (B (A) )pentamidine. T-2307 and (B) pentamidine. In order to assess the mechanism of action of T-2307 against yeast, Shibata et al. con- ducted a series of experiments [13]. To investigate the effects of T-2307 on the mitochon- drial function in S. cerevisiae and C. albicans, the accumulation of the fluorescent dye Mi- toTracker Red CMXRos (MTR), a mitochondrial marker that concentrates in active mito- chondria by membrane potential, was evaluated by microscopy. The presence of T-2307 at a concentration of 1 µM resulted in a less intense staining of mitochondria by MTR, indicating that the mitochondrial function had collapsed. These results were similar to those observed with carbonyl cyanide m-chlorophyenylhydrazone (CCCP), a protono- phore and uncoupler of oxidative phosphorylation. In both S. cerevisiae and C. albicans, the number of whole cells with intense staining of the mitochondria decreased in the presence of T-2307 in a concentration-dependent fashion. In addition, a gradual and dose-depend- ent collapse of the mitochondrial membrane potential was also noted in mitochondria iso- lated from S. cerevisiae that were exposed to T-2307 or pentamidine. However, the T-2307 concentration required to cause a collapse in the membrane potential of at least 50% (30 µM) was markedly higher than the concentration required to inhibit the growth of the isolate (MIC 0.002 µM, or 0.001 µg/mL). With pentamidine, a reduction in the mitochon- drial membrane potential of at least 50% occurred at a concentration of 5 µM, while the MIC against S. cerevisiae was reported to be 1.5 µM, or 0.5 µg/mL. 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 me- dium via transporter mediated systems [16]. Subsequent work has indicated that T-2307 transport into C. albicans occurs through a high-affinity spermine and spermidine transport system that is regulated by Agp2, a plasma membrane protein involved in the update of L-carnitine and polyamines and other substrates
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