Inhibition of Distinct Proline- or N-Acetylglucosamine-Induced Hyphal Formation Pathways by Proline Analogs in Candida albicans.

Tatsuki Sato,Rinji Akada,Hisashi Hoshida,Stanley Brul

doi:10.1155/2020/7245782

Abstract

Candida albicans undergoes a yeast-to-hyphal transition that has been recognized as a virulence property as well as a turning point leading to biofilm formation associated with candidiasis. It is known that yeast-to-hyphal transition is induced under complex environmental conditions including temperature (above 35°C), pH (greater than 6.5), CO2, N-acetylglucosamine (GlcNAc), amino acids, RPMI-1640 synthetic culture medium, and blood serum. To identify the hyphal induction factor in the RPMI-1640 medium, we examined each component of RPMI-1640 and established a simple hyphal induction condition, that is, incubation in L-proline solution at 37°C. Incubation in GlcNAc solution alone, which is not contained in RPMI-1640, without any other materials was also identified as another simple hyphal induction condition. To inhibit hyphal formation, proline and GlcNAc analogs were examined. Among the proline analogs used, L-azetidine-2-carboxylic acid (AZC) inhibited hyphal induction under both induction conditions, but L-4-thiazolidinecarboxylic acid (T4C) specifically inhibited proline-induced hyphal formation only, while α-N-methyl-L-proline (mPro) selectively inhibited GlcNAc-induced hyphal formation. Hyphal formation in fetal bovine serum was also inhibited by AZC or T4C together with mPro without affecting the proliferation of yeast form. These results indicate that these proline analogs are ideal inhibitors of yeast-to-hyphal transition in C. albicans.

Highlights

Candida albicans is an opportunistic fungal pathogen that commonly exists as a benign member of the human microbiome
To identify key environmental factors and components of hyphal induction in C. albicans, we first confirmed whether the C. albicans JCM1542 strain transformed to hyphal form in the RPMI-1640 medium, a completely chemically defined medium that is known as the basic hyphal induction condition [6, 11,12,13]
After cells were incubated in RPMI1640 medium at 37°C for 24 h, C. albicans showed hyphal morphology (Figure 1(a))

Summary

Introduction

Candida albicans is an opportunistic fungal pathogen that commonly exists as a benign member of the human microbiome. C. albicans can assume at least three distinct morphologies: yeast like, pseudohyphae, and true hyphae, where the latter two are commonly referred to as filamentous morphologies [3,4,5,6]. Filamentous forms of C. albicans were considered pathogenic, whereas the yeast form was primarily viewed as commensal. Inhibition of yeast-to-hyphal transition is a promising target to prevent candidiasis. In this direction, nontoxic small molecules that inhibit C. albicans yeast-to-hyphal transition and hyphal growth were screened for the development of antifungal agents [7,8,9,10]

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Discussion

Conclusion