The atypical antipsychotic aripiprazole alters the outcome of disseminated Candida albicans infections.

Invasive fungal infections impose an enormous clinical, social, and economic burden on humankind. One of the most common species responsible for invasive fungal infections is Candida albicans. More than 30% of patients with disseminated candidiasis fail therapy with existing antifungal drugs, including the widely used azole class. We previously identified a collection of 13 medications that antagonize the activity of the azoles on C. albicans. Although gain-of-function mutations responsible for antifungal resistance are often associated with reduced fitness and virulence, it is currently unknown how exposure to azole antagonistic drugs impacts C. albicans physiology, fitness, or virulence. In this study, we examined how exposure to seven azole antagonists affects C. albicans phenotype and capacity to cause disease. Most of the azole antagonists appear to have little impact on fungal growth, morphology, stress tolerance, or gene transcription. However, aripiprazole had a modest impact on C. albicans hyphal growth and increased cell wall chitin content. It also aggravated the disseminated C. albicans infections in mice. This effect was abrogated in immunosuppressed mice, indicating that it is at least in part dependent upon host immune responses. Collectively, these data provide proof of principle that unanticipated drug-fungus interactions have the potential to influence the incidence and outcomes of invasive fungal disease.

The atypical antipsychotic aripiprazole alters the outcome of disseminated Candida albicans infections.

Invasive fungal infections (IFIs) impose an enormous clinical, social, and economic burden on humankind. For many IFIs, ≥ 30% of patients fail therapy with existing antifungal drugs, including the widely used azole class. We previously identified a collection of 13 approved medications that antagonize azole activity. While gain-of-function mutants resulting in antifungal resistance are often associated with reduced fitness and virulence, it is currently unknown how exposure to azole antagonistic drugs impact C. albicans physiology, fitness, or virulence. In this study, we examined how exposure to azole antagonists affected C. albicans phenotype and capacity to cause disease. We discovered that most of the azole antagonists had little impact on fungal growth, morphology, stress tolerance, or gene transcription. However, aripiprazole had a modest impact on C. albicans hyphal growth and increased cell wall chitin content. It also worsened the outcome of disseminated infections in mice at human equivalent concentrations. This effect was abrogated in immunosuppressed mice, indicating an additional impact of aripiprazole on host immunity. Collectively, these data provide proof-of-principle that unanticipated drug-fungus interactions have the potential to influence the incidence and outcomes of invasive fungal disease.

Titration of C-5 Sterol Desaturase Activity Reveals Its Relationship to Candida albicans Virulence and Antifungal Susceptibility Is Dependent upon Host Immune Status.

The azole antifungals inhibit sterol 14α-demethylase (S14DM), which depletes cellular ergosterol and promotes synthesis of the dysfunctional lipid 14α-methylergosta-8,24(28)-dien-3ß,6α-diol, ultimately arresting growth. Mutations that inactivate sterol Δ5,6-desaturase (Erg3p), the enzyme that produces the sterol-diol upon S14DM inhibition, enhances Candida albicans growth in the presence of the azoles. However, erg3 null mutants are sensitive to some physiological stresses and can be less virulent than the wild type. These fitness defects may disfavor the selection of null mutants within patients. The objective of this study was to investigate the relationship between Erg3p activity, C. albicans pathogenicity, and the efficacy of azole therapy. An isogenic panel of strains was constructed that produce various levels of the ERG3 transcript. Analysis of the sterol composition confirmed a correspondingly wide range of Erg3p activity. Phenotypic analysis revealed that even moderate reductions in Erg3p activity are sufficient to greatly enhance C. albicans growth in the presence of fluconazole in vitro without impacting fitness. Moreover, even low levels of Erg3p activity are sufficient to support full virulence of C. albicans in the mouse model of disseminated infection. Finally, while the antifungal efficacy of fluconazole was similar for all strains in immunocompetent mice, there was an inverse correlation between Erg3p activity and the capacity of C. albicans to endure treatment in leukopenic mice. Collectively, these results establish that relative levels of Erg3p activity determine the antifungal efficacy of the azoles upon C. albicans and reveal the critical importance of host immunity in determining the clinical impact of this resistance mechanism. IMPORTANCE Mutations that completely inactivate Erg3p enable the prevalent human pathogen C. albicans to endure the azole antifungals in vitro. However, such null mutants are less frequently identified in azole-resistant clinical isolates than other resistance mechanisms, and previous studies have reported conflicting outcomes regarding antifungal resistance of these mutants in animal models of infection. The results of this study clearly establish a direct correlation between the level of Erg3p activity and the antifungal efficacy of fluconazole within a susceptible mammalian host. In addition, low levels of Erg3p activity are apparently more advantageous for C. albicans survival of azole therapy than complete loss of function. These findings suggest a more nuanced but more important role for Erg3p as a determinant of the clinical efficacy of the azole antifungals than previously appreciated. A revised model of the relationship between Erg3p activity, host immunity, and the antifungal susceptibility of C. albicans is proposed.