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Candida albicans is a polymorphic fungus which is the predominant cause of superficial and deep tissue fungal infections. This microorganism has developed efficient strategies to invade the host and evade host defense systems. However, the host immune system will be prepared for defense against the microbe by recognition of receptors, activation of signal transduction pathways and cooperation of immune cells. As a consequence, C. albicans could either be eliminated by immune cells rapidly or disseminate hematogenously, leading to life-threatening systemic infections. The interplay between Candida albicans and the host is complex, requiring recognition of the invaded pathogens, activation of intricate pathways and collaboration of various immune cells. In this review, we will focus on the effects of innate immunity that emphasize the first line protection of host defense against invaded C. albicans including the basis of receptor-mediated recognition and the mechanisms of cell-mediated immunity.

Acquired resistance in Candida albicans brings about a serious challenge to the clinical application of azoles, so it is urgent to elucidate the mechanisms of azole resistance to improve the therapeutic efficiency. In the aim of searching for the potential targets mediating fluconazole resistance, we screened a mutant library of 48 transcription factor deletion Candida albicans strains. The screening results showed that hap2Δ/Δ mutants were significantly more susceptible to azoles, especially to miconazole (MCZ). Under MCZ treatment, the intracellular reactive oxygen species (ROS) were significantly higher in hap2Δ/Δ mutants compared to the control strain SN250. The addition of antioxidants reversed the MCZ-sensitive phenotype caused by the deletion of HAP2. Consistently, the expression of antioxidases responsible for scavenging ROS was shown to decrease in hap2Δ/Δ mutants, suggesting that the transcription factor Hap2p is involved in the regulation of oxidative stress responses in C. albicans. In addition, HAP2 deficiency also resulted in impaired mitochondrial function and affected cellular energy supply, which may be related to the iron deficiency regulated by HAP complex. HAP2 disruption also decreased efflux-mediated resistance of C. albicans, as demonstrated by a significant decrease in Cdr1p expression and a slight decrease in Mdr1p expression in hap2Δ/Δ strains under the action of MCZ. The above results indicate that the transcription factor Hap2p was required for the resistance of C. albicans to azoles, which could provide a new strategy to solve the clinical azoles resistance. [ABSTRACT FROM AUTHOR]

Nowadays, discovering new skeleton antifungal drugs is the direct way to address clinical fungal infections. Pyrylium salt SM21 was screened from a library containing 50,240 small molecules. Several studies about the antifungal activity and mechanism of SM21 have been reported, but the structure–activity relationship of pyrylium salts was not clear. To explore the chemical space of antifungal pyrylium salt SM21, a series of pyrylium salt derivatives were designed and synthesized. Their antifungal activity and structure-activity relationships (SAR) were investigated. Compared with SM21, most of the synthesized compounds exhibited equivalent or improved antifungal activities against Candida albicans in vitro. The synthesized compounds, such as XY10, XY13, XY14, XY16 and XY17 exhibited comparable antifungal activities against C. albicans with MIC values ranging from 0.47 to 1.0 μM. Fortunately, a compound numbered XY12 showed stronger antifungal activities and lower cytotoxicity was obtained. The MIC of compound XY12 against C. albicans was 0.24 μM, and the cytotoxicity decreased 20-fold as compared to SM21. In addition, XY12 was effective against fluconazole-resistant C. albicans and other pathogenic Candida species. More importantly, XY12 could significantly increase the survival rate of mice with a systemic C. albicans infection, which suggested the good antifungal activities of XY12 in vitro and in vivo. Our results indicated that structural modification of pyrylium salts could lead to the discovery of new antifungal drugs. [ABSTRACT FROM AUTHOR]