Identification of New Antifungal Agents Targeting Chitin Synthesis by a Chemical-Genetic Method.

Li Li,Zhu Zhu,Wang Wang,Sun Sun,Bian Bian,Si Si

doi:10.3390/molecules24173155

Abstract

Fungal infection is a leading cause of mortality in immunocompromised population; thus, it is urgent to develop new and safe antifungal agents. Different from human cells, fungi have a cell wall, which is composed mainly of polysaccharide glucan and chitin. The unique cell wall structure is an ideal target for antifungal drugs. In this research, a chemical-genetic method was used to isolate antifungal agents that target chitin synthesis in yeast cells. From a compound library, we isolated two benzothiazole compounds that showed greater toxicity to yeast mutants lacking glucan synthase Fks1 compared to wild-type yeast cells and mutants lacking chitin synthase Chs3. Both of them inhibited the activity of chitin synthase in vitro and reduced chitin level in yeast cells. Besides, these compounds showed clear synergistic antifungal effect with a glucan synthase inhibitors caspofungin. Furthermore, these compounds inhibited the growth of Saccharomyces cerevisiae and opportunistic pathogen Candida albicans. Surprisingly, the genome-wide mass-spectrometry analysis showed decreased protein level of chitin synthases in cells treated with one of these drugs, and this decrease was not a result of downregulation of gene transcription. Therefore, we successfully identified two new antifungal agents that inhibit chitin synthesis using a chemical-genetic method.

Highlights

Fungal infection is a leading cause of mortality in the immunocompromised population, such as patients who undergo anticancer chemotherapy, radiation therapy, parenteral nutrition, or organ transplant [1]
Cerevisiae, Fks1 protein is the catalytic subunit of β-1,3-glucan synthase, while chitin synthase Chs3 catalyzes chitin synthesis
Deletion of either FKS1 or CHS3 in budding yeast does not lead to cell death, yeast cells lacking both genes cannot survive [18], which supports the idea that simultaneous reduction in β-1,3-glucan and chitin synthesis cause cell death

Summary

Introduction

Fungal infection is a leading cause of mortality in the immunocompromised population, such as patients who undergo anticancer chemotherapy, radiation therapy, parenteral nutrition, or organ transplant [1]. This population includes patients infected with HIV, which disrupts the immune system [2]. In contrast to the increased incidence of fungal infections, the number of efficient and less toxic antifungal antibiotics is limited. The increased use of antifungal agents leads to the emergence of drug-resistant fungal strains [3,4]. It is urgent to develop new and safe antifungal agents. Fungi have a cell wall structure, which is an ideal target for antifungal drugs

Methods

Results

Conclusion