Development of Carbazole Derivatives Compounds against Candida albicans: Candidates to Prevent Hyphal Formation via the Ras1-MAPK Pathway.

Young-Kwang Park,Hee-Yoon Lee,Joon Kim,Hag-Dong Kim,Jisoo Shin

doi:10.3390/jof7090688

Abstract

Morphogenesis contributes to the virulence of the opportunistic human fungal pathogen Candida albicans. Ras1-MAPK pathways play a critical role in the virulence of C. albicans by regulating cell growth, morphogenesis, and biofilm formation. Ume6 acts as a transcription factor, and Nrg1 is a transcriptional repressor for the expression of hyphal-specific genes in morphogenesis. Azoles or echinocandin drugs have been extensively prescribed for C. albicans infections, which has led to the development of drug-resistant strains. Therefore, it is necessary to develop new molecules to effectively treat fungal infections. Here, we showed that Molecule B and Molecule C, which contained a carbazole structure, attenuated the pathogenicity of C. albicans through inhibition of the Ras1/MAPK pathway. We found that Molecule B and Molecule C inhibit morphogenesis through repressing protein and RNA levels of Ras/MAPK-related genes, including UME6 and NRG1. Furthermore, we determined the antifungal effects of Molecule B and Molecule C in vivo using a candidiasis murine model. We anticipate our findings are that Molecule B and Molecule C, which inhibits the Ras1/MAPK pathway, are promising compounds for the development of new antifungal agents for the treatment of systemic candidiasis and possibly for other fungal diseases.

Highlights

Candida albicans is a commensal fungal pathogen that causes opportunistic infections in humans
Molecule B and Molecule C both showed the same minimum inhibitory concentrations (MICs) (4 μg/mL) in BY4741, a wild-type strain of S. cerevisiae (Figure S1b). These results suggest that Molecule B and Molecule C have growth inhibitory activity against C. albicans, including strains that are resistant to existing drugs
Many studies have suggested that the processes of biofilm formation [33] and morphogenesis [44] of C. albicans are closely related to pathogenicity

Summary

Introduction

Candida albicans is a commensal fungal pathogen that causes opportunistic infections in humans. Morphogenesis is critical for the pathogenicity of C. albicans [4,5] It has two main forms: yeast and hyphal. The dimorphism that allows the ability to switch between yeast and hyphal growth forms is essential for pathogenicity. Morphogenesis has various environmental cues, such as nutrient limitation, alkaline pH, quorum sensing molecules, serum, elevated temperature, and elevated CO2 [7,8]. In C. albicans, MAPK and Ras/PKA-dependent pathways regulate nutrient sensing and acquisition, stress response, and pathogenesis, as well as play a potent role in hyphal formation [10,11]. The small GTPase Ras in this fungus affects both pathways and acts as a switch for hyphal formation signals, such as serum, elevated temperature, and nutrient limitation [11]. The transcriptional repressor Nrg works with Ume as a negative feedback loop to control the expression of HSGs in hyphal growth environmental signals [13,14]

Methods

Results

Conclusion