Advances in antifungal development: Discovery of new drugs and drug repurposing

Authors: Kim, Jong Heon; CHENG, LUISA - Former ARS Employee; LAND, KIRKWOOD - University Of The Pacific

Submitted to: Pharmaceuticals
Publication Type: Review Article
Publication Acceptance Date: 6/23/2022
Publication Date: 6/24/2022
Citation: Kim, J., Cheng, L.W., Land, K.M. 2022. Advances in antifungal development: Discovery of new drugs and drug repurposing. Pharmaceuticals. 15(7). Article 787. https://doi.org/10.3390/ph15070787.
DOI: https://doi.org/10.3390/ph15070787

Interpretive Summary: This Special Issue of Pharmaceuticals describes recent advances accomplished in the field of antifungal development, especially the discovery of new drugs and drug repurposing. The subjects of the published articles include: new drugs from natural or synthetic sources, design, synthesis and antifungal evaluation of newly-synthesized compounds, novel nanotechnology systems for drug delivery, drug repurposing for fungal control and/or overcoming the multidrug-resistant fungi, repurposing antifungal drugs for antiviral therapy, evaluation of differential antifungal efficacy of echinocandins, among others. Infectious diseases caused by fungal pathogens, such as aspergillosis, candidiasis or cryptococcus, are recurring problems. Current antifungal interventions often exhibited very limited efficacy in treating fungal infections, partly because the spectrum of the activity of conventional systemic antifungal drugs is narrow while the development of new antifungal drugs has become stagnant; azole and polyene drugs were introduced before 1980, whereas the echinocandin drug CAS was approved for the clinical uses since 2000. The research articles and reviews presented in this Special Issue provide useful information and insight for the development of new antifungal drugs or intervention strategies. Identification of new, safe molecules, cellular targets, as well as elucidation of their antifungal mechanisms of action will further the effective control of fungal pathogens, especially those resistant to current therapeutic agents.

Technical Abstract: Increased incidences of pathogen resistance to the conventional antifungal interventions make fungal diseases a global human health concern. For instance, sequential combination therapy is one of the strategies for effective control of fungi. However, prior exposure of fungal pathogens, such as Candida species or Aspergillus fumigatus, to azole drugs lowered the susceptibility of the fungal biofilms or germlings to polyenes such as amphotericin B (AMB). It’s been determined that azole drugs could potentiate fungal tolerance to AMB via heat-shock protein 90 (Hsp90)-mediated oxidative stress defenses in pathogens. Azoles are also applied in crop fields as fungicides to control plant fungal pathogens; for instance, more than 25% of current fungicide sales are azoles. From the clinical perspective, increased application of agricultural fungicides provides environmental selection pressure for the development of azole-resistant fungal pathogens such as Aspergillus fumigatus possessing the TR34/L98H mutation, which resulted in the recent placement of azole-resistant A. fumigatus on the microorganism “watchlist (antibiotic resistance threat)” by the United States Centers for Disease Control and Prevention (CDC). In view of the difficulties to treat invasive fungal infections, the development of new, alternative antifungal strategies that are efficient and appropriate measures are urgently needed. Antifungal drug repurposing is the repositioning process of already marketed medicinal drugs developed for treating human diseases to cure fungal infections. The key merit of drug repurposing is that the mechanisms of action, cellular targets, or safety of the marketed drugs are already known, thus enabling accelerated regulatory approval once antifungal efficacy is determined. Notably, drug repurposing for treating the emerging multidrug resistant (MDR) fungus such as Candida auris, Aspergillus or Cryptococcus species has been discussed, addressing the potential of antifungal drug repurposing to treat the difficult fungal pathogens. In this Special Issue, thirteen works (seven original research articles, six reviews) were published on the recent advances in antifungal development, providing current tools, methods, strategies or insights on antifungal therapy.