The Future of Antifungal Drug Therapy: Novel Compounds and Targets

Abstract

Fungal infections are a universal problem and are routinely associated with high morbidity and mortality rates in immunocompromised patients. Existing therapies comprise five different classes of antifungal agents, four of which target the synthesis of ergosterol and cell wall glucans. However, the currently available antifungals have many limitations including poor oral bioavailability, narrow therapeutic indexes, and emerging drug resistance resulting from their use, thus making it essential to investigate the development of novel drugs which can overcome these limitations and add to the antifungal armamentarium. Advances have been made in antifungal drug discovery research and development over the past few years as evidenced by the presence of several new compounds currently in various stages of development. In the following review we provide a comprehensive summary of compounds aimed at novel molecular target(s). We also briefly describe potential pathways, relevant for fungal pathogenesis, that can be considered for drug development in the near future.

Role of Protein Glycosylation in Interactions of Medically Relevant Fungi with the Host

“…Moreover, fosmanogepix did not affect the activity of the Gwt1 human ortholog, and thus inositol acylation of GPI occurred in its presence, suggesting selectivity against the fungal enzyme [92]. Since fosmanogepix prevents experimental fungal infections and has been successful in clinical phase 1 studies, it is now in phase 2 clinical trials for invasive candidiasis and aspergillosis [138,139].…”

Isoeugenol Affects Expression Pattern of Conidial Hydrophobin Gene RodA and Transcriptional Regulators MedA and SomA Responsible for Adherence and Biofilm Formation in Aspergillus fumigatus

“…The mainstay antifungal drugs against A. fumigatus infections mainly target fungal cell membrane components and enzymes involved in its biosynthesis. Despite availability of the antifungal drugs, there are many limitations, including poor oral bioavailability, narrow therapeutic indices and emerging drug resistance resulting from their excessive use (Hagiwara et al 2016;Mota Fernandes et al 2021). Thus, the discovery of a novel antifungal with broad-spectrum activity, low toxicity, minimal side effects and enhanced bioavailability is highly warranted (Brauer et al 2019).…”

Solid and Semisolid Innovative Formulations Containing Miconazole-Loaded Solid Lipid Microparticles to Promote Drug Entrapment into the Buccal Mucosa

“…Trehalose (α-D-glucopyranosyl-α-D-glucopyranoside) is a nonreducing sugar widely used in food, cosmetics and pharmaceutics for its unique ability to sustain and preserve a wide array of biological molecules due to its functions as a stress protectant, preventing protein degradation and preserving the cell membrane structure under stress conditions [ 34 ]. In addition, new findings suggest that the targeting of the trehalose pathway might compromise fungal viability and virulence in Cryptococcus neoformans [ 35 ], indicating this sugar as a potential antifungal agent [ 36 ]. Finally, trehalose possesses sweetening properties suitable for diabetic patients, which could improve the palatability of the formulation.…”