Abstract
Discovering new drugs for treatment of invasive fungal infections is an enduring challenge. There are only three major classes of antifungal agents, and no new class has been introduced into clinical practice in more than a decade. However, recent advances in our understanding of the fungal life cycle, functional genomics, proteomics, and gene mapping have enabled the identification of new drug targets to treat these potentially deadly infections. In this paper, we examine amino acid transport mechanisms and metabolism as potential drug targets to treat invasive fungal infections, including pathogenic yeasts, such as species of Candida and Cryptococcus, as well as molds, such as Aspergillus fumigatus. We also explore the mechanisms by which amino acids may be exploited to identify novel drug targets and review potential hurdles to bringing this approach into clinical practice.
Highlights
Recent advances in our understanding of the fungal life cycle, functional genomics, and proteomics have enabled the identification of multiple potential new drug targets that could bolster the arsenal of available options to treat invasive fungal infections (IFIs), which include pathogenic yeasts, molds, and thermally-dimorphic fungi [1,2,3]
Three major classes of antifungal agents are currently available to clinicians to treat IFI: (1) the polyene amphotericin B-deoxycholate, which binds fungal cell membrane ergosterol leading to cell lysis; (2) azoles that inhibit ergosterol biosynthesis; and (3) echinocandins that inhibit fungal (1→3)-β-D-glucan cell wall biosynthesis [7,8]
The widespread use of immunosuppressants, hematopoietic stem cell transplantation and solid organ transplantation, and novel immunomodulators in clinical practice, has led to an expanding population of patients who are at risk for invasive fungal infection
Summary
Recent advances in our understanding of the fungal life cycle, functional genomics, and proteomics have enabled the identification of multiple potential new drug targets that could bolster the arsenal of available options to treat invasive fungal infections (IFIs), which include pathogenic yeasts, molds, and thermally-dimorphic fungi [1,2,3]. The drug was evaluated in escalating dosages against experimental invasive candidiasis (both esophageal and oropharyngeal models of disease) caused by fluconazole-resistant C. albicans in rabbits with immune impairment These rabbits were divided in a manner similar to other studies involving invasive candidiasis: some rabbits received icofungipen at 4, 10, 25, or 50 mg/kg of body weight/day via intravenous (iv) twice daily injections; other rabbits received FLC at 2 mg/kg/day via iv twice daily injections. Another group received amphotericin B (DAMB) iv at 0.5 mg/kg/day, and these were all compared to untreated controls to assess dose-dependent antifungal activity.
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