Transcriptional responses of Candida glabrata biofilm cells to fluconazole are modulated by the carbon source

Abstract

Candida glabrata is an important human fungal pathogen known to trigger serious infections in immune-compromised individuals. Its ability to form biofilms, which exhibit high tolerance to antifungal treatments, has been considered as an important virulence factor. However, the mechanisms involving antifungal resistance in biofilms and the impact of host niche environments on these processes are still poorly defined. In this study, we performed a whole-transcriptome analysis of C. glabrata biofilm cells exposed to different environmental conditions and constraints in order to identify the molecular pathways involved in fluconazole resistance and understand how acidic pH niches, associated with the presence of acetic acid, are able to modulate these responses. We show that fluconazole treatment induces gene expression reprogramming in a carbon source and pH-dependent manner. This is particularly relevant for a set of genes involved in DNA replication, ergosterol, and ubiquinone biosynthesis. We also provide additional evidence that the loss of mitochondrial function is associated with fluconazole resistance, independently of the growth condition. Lastly, we propose that C. glabrata Mge1, a cochaperone involved in iron metabolism and protein import into the mitochondria, is a key regulator of fluconazole susceptibility during carbon and pH adaptation by reducing the metabolic flux towards toxic sterol formation. These new findings suggest that different host microenvironments influence directly the physiology of C. glabrata, with implications on how this pathogen responds to antifungal treatment. Our analyses identify several pathways that can be targeted and will potentially prove to be useful for developing new antifungals to treat biofilm-based infections.

Nanocarriers of Miconazole or Fluconazole: Effects on Three-Species Candida Biofilms and Cytotoxic Effects In Vitro

“…Concerning the mechanism of action of FLZ, this antifungal agent inhibits the synthesis of ergosterol and enzymes of the cytochrome P-450 complex (including CYP34A), affecting fungal membrane fluidity, and cell growth and proliferation [21]. It should be noted that IONPs-CS-FLZ was not able to overcome the problem of intrinsic resistance of C. glabrata to FLZ, as detailed in previous studies [22,23], considering that FLZ (free or conjugated to the compound IONPs-CS) did not reduce CFUs of C. glabrata (Figure 1A). In this sense, a previous study showed that FLZ and IONPs-CS-FLZ were effective in reducing cultivable cells of single biofilms of C. albicans and C. glabrata [11], though at a FLZ concentration (1250 µg/mL) 8-32 times higher than those used in the present study.…”

Adapting to survive: How Candida overcomes host-imposed constraints during human colonization

“…In C. albicans, the uptake of lactate is mediated by Jen transporters [51,53], while Ato transporters are potentially involved in the transport of acetate in both C. albicans and C. glabrata [52,54] (Fig 2c). These two transporter families are strongly induced after phagocytosis [51,52], and they modulate biofilm formation and resistance to antifungal drugs in both C. albicans and C. glabrata [54][55][56]. In particular, exposure to lactate has been shown to trigger the masking of β-glucan, a major pathogen-associated molecular pattern (PAMP), in several Candida species [57].…”

Candida glabrata Antifungal Resistance and Virulence Factors, a Perfect Pathogenic Combination

“…In addition, they can form a germ tube and they possess phenotypic and genotypic variability [ 142 ]. Such virulence factors grant them the ability to evade the host’s immune response and generate antifungal resistance [ 147 , 149 ].…”