Recent Progress in the Discovery of Antifungal Agents Targeting the Cell Wall

Abstract

Due to the limit of available treatments and the emergence of drug resistance in the clinic, invasive fungal infections are an intractable problem with high morbidity and mortality. The cell wall, as a fungi-specific structure, is an appealing target for the discovery and development of novel and low-toxic antifungal agents. In an attempt to accelerate the discovery of novel cell wall targeted drugs, this Perspective will provide a comprehensive review of the progress made to date on the development of fungal cell wall inhibitors. Specifically, this review will focus on the targets, discovery process, chemical structures, antifungal activities, and structure–activity relationships. Although two types of cell wall antifungal agents are clinically available or in clinical trials, it is still a long way for the other cell wall targeted inhibitors to be translated into clinical applications. Future efforts should be focused on the identification of inhibitors against novel conserved cell wall targets.

Jerveratrum-Type Steroidal Alkaloids Inhibit β-1,6-Glucan Biosynthesis in Fungal Cell Walls

“…Among the antifungal agents currently used for mycoses, polyenes and azoles, pyrimidines, and echinocandins bind or block the synthesis of ergosterol, disrupt DNA/RNA function, and block β-1,3-glucan biosynthesis, respectively ( 10 ). Drug development tends to focus on echinocandins, which act on the fungal cell wall ( 10 , 11 ), are essential for fungal growth, and are absent from human cells ( 12 , 13 ). The fungal cell wall is mainly composed of β-1,3-glucan, β-1,6-glucan, chitin, and mannoprotein ( 10 , 14 ).…”

“…The fungal cell wall is mainly composed of β-1,3-glucan, β-1,6-glucan, chitin, and mannoprotein ( 10 , 14 ). Drug discovery studies have focused on β-1,3-glucan biosynthesis ( 10 , 11 ). The echinocandins, including echinocandin B (EB), caspofungin, micafungin, and anidulafungin, bind to and inhibit the catalytic subunit Fks1/2 of β-1,3-glucan synthase ( 10 , 11 , 15 , 16 ).…”

Paeonol Disrupts the Integrity of Aspergillus flavus Cell Walls via Releasing Surface Proteins, Inhibiting the Biosynthesis of β-1,3-Glucan and Promoting the Degradation of Chitin, and an Identification of Cell Surface Proteins

“…The fungal cell wall is composed of various compounds, such as polysaccharides, proteins, fats, and ions, and is essential in maintaining cell homeostasis and protecting cells [ 5 , 6 ]. As a unique and dynamic structure, fungal cell wall has been extensively studied and considered as an attractive antimicrobial target [ 6 , 7 , 8 ]. Although there has been no report on the detailed components of A. flavus cell walls, in our previous study, they are assumed to be organized into two layers [ 9 ], similar to Aspergillus fumigatus ( A. fumigatus ).…”

Identification of a novel SPT inhibitor WXP-003 by docking-based virtual screening and investigation of its anti-fungi effect

“…fluconazole, ketoconazole), echinocandins (e.g. micafungin) and 5-fluorocytosine 4 . With the extensive use of conventional antifungal agents, the emerging azole-resistant fungi make the problem more intractable [5][6][7] .…”