Beyond Ergosterol: Strategies for Combatting Antifungal Resistance in Aspergillus fumigatus and Candida auris

Abstract

Aspergillus fumigatus and Candida auris are historically problematic fungal pathogens responsible for systemic infections and high mortality rates, especially in immunocompromised populations. The three antifungal classes that comprise our present day armamentarium have facilitated efficacious treatment of these fungal infections in past decades, but their potency has steadily declined over the years as resistance to these compounds has accumulated. Importantly, pan-resistant strains of Candida auris have been observed in clinical settings, leaving affected patients with no treatment options and a death sentence. Many compounds in the ongoing antifungal drug discovery pipeline, similar to those within our aforementioned trinity, are predicated on the binding or inhibition of ergosterol. Recurring accounts of resistance to antifungals targeting this pathway suggest optimization of ergosterol-dependent antifungals is likely not the best solution for the long-term. This review aims to present several natural products with novel or underexplored biological targets, as well as similarly underutilized drug discovery strategies to inspire future biological investigations and medicinal chemistry campaigns.

Keywords: Antifungals; Antimicrobial Resistance; Natural Products; Total Synthesis.

Figure 1.

Representative compounds from our current armamentarium. *Ketoconazole is typically prepared and administered as a racemic mixture.

Figure 2.

Antifungals recently approved for use or currently in clinical trials.

Figure 3.

Compounds targeting novel or understudied fungal machinery.

Figure 4.

Anti-virulence antifungals and related stilbenoid natural products.

Figure 5.

Antifungal natural products identified by the CaFT. * represents an undefined stereocenter.

Figure 6.

Antifungal natural products studied using genomics-based approaches. * represents an undefined stereocenter.

Figure 7.

Total syntheses of harzianic acid (A), (±)-ilicicolin H (B), and (+)-sambutoxin (C).

Figure 8.

Total synthesis efforts towards the tetrandrines (A) and parnafungins (B).