Small molecules for combating multidrug-resistant superbug Candida auris infections

Abstract

Candida auris is emerging as a major global threat to human health. C. auris infections are associated with high mortality due to intrinsic multi-drug resistance. Currently, therapeutic options for the treatment of C. auris infections are rather limited. We aim to provide a comprehensive review of current strategies, drug candidates, and lead compounds in the discovery and development of novel therapeutic agents against C. auris. The drug resistance profiles and mechanisms are briefly summarized. The structures and activities of clinical candidates, drug combinations, antifungal chemosensitizers, repositioned drugs, new targets, and new types of compounds will be illustrated in detail, and perspectives for guiding future research will be provided. We hope that this review will be helpful to prompting the drug development process to combat this fungal pathogen.

Keywords: Antifungal agents; Antifungal targets; Candida auris; Drug resistance; Virulence factors.

Graphical abstract

Figure 1

Chemical structures of clinically available antifungal agents.

Figure 2

Resistance mechanisms to antifungal agents in C. auris. Mutation of targets, overexpression of efflux pumps, and alteration of membrane components are associated with the resistance of C. auris to azoles (A), polyenes (B), echinocandins (C), and flucytosine (D). The formation of biofilms is a general mechanism of antifungal resistance (E).

Figure 3

Chemical structures of investigated antifungal agents for the treatment of C. auris infections.

Figure 4

Chemical structures of marketed drugs and chemosensitizers for the combination treatment of C. auris infections.

Figure 5

Chemical structures of marketed drugs and derivatives with inhibitory activity against C. auris infections.

Figure 6

Crystal structure of Sec14p (A, PDB code: 6F0E) and a proposed binding model of turbinmicin with Sec14p (B). The magenta mesh indicates turbinimicin, and the dashed green lines represent hydrogen bonding interactions.

Figure 7

Chemical structure of GW461484A (A), crystal structure of Yck2 (B, PDB code: 6U6A), and the binding mode of GW461484A with Yck2 (C). The orange molecule indicates compound GW461484A.

Figure 8

Chemical structure of BSM and CE (A), crystal structure of AHAS (B, PDB code: 6DEL), and the binding mode of CE with AHAS (C). The green molecule indicate compound CE. Solid brown lines, dashed blue lines, and dashed red lines represent hydrophobic, hydrogen bonding and π‒π stacking interactions, respectively.

Figure 9

Chemical structures of new chemotypes with inhibitory activity against C. auris.