sirolimus and Candidiasis

The pathogenic yeast Candida albicans, a member of the mucosal microbiota, is responsible for a large spectrum of infections, ranging from benign thrush and vulvovaginitis in both healthy and immunocompromised individuals to severe, life-threatening infections in immunocompromised patients. A striking feature of C. albicans is its ability to grow as budding yeast and as filamentous forms, including hyphae and pseudohyphae. The yeast-to-hypha transition contributes to the overall virulence of C. albicans and may even constitute a target for the development of antifungal drugs. Indeed, impairing morphogenesis in C. albicans has been shown to be a means to treat candidiasis. Additionally, a large number of small molecules such as farnesol, fatty acids, rapamycin, geldanamycin, histone deacetylase inhibitors, and cell cycle inhibitors have been reported to modulate the yeast-to-hypha transition in C. albicans. In this minireview, we take a look at molecules that modulate morphogenesis in this pathogenic yeast. When possible, we address experimental findings regarding their mechanisms of action and their therapeutic potential. We discuss whether or not modulating morphogenesis constitutes a strategy to treat Candida infections.

Topics: Animals; Anti-Bacterial Agents; Bacteriocins; Benzoquinones; Candida albicans; Candidiasis; Cell Cycle; Cyclooxygenase Inhibitors; Farnesol; Fatty Acids; Histone Deacetylase Inhibitors; Humans; Lactams, Macrocyclic; Morphogenesis; Sirolimus; Virulence

In this study, 18 predicted membrane-localized ABC transporters of Candida glabrata were deleted individually to create a minilibrary of knockouts (KO). The transporter KOs were analyzed for their susceptibility toward antimycotic drugs. Although Cg

Topics: Antifungal Agents; ATP-Binding Cassette Transporters; Azoles; Calcineurin; Candida glabrata; Candidiasis; Drug Resistance, Fungal; Fluconazole; Fungal Proteins; Membrane Transport Proteins; Microbial Sensitivity Tests; Nitrogen; Oligomycins; Sirolimus

Calcium-permeable transient receptor potential (TRP) channels exist in eukaryotic cells from yeasts to animals and plants. and they act as sensors for various stresses. Arabidopsis thaliana calcium permeable stress-gated cation channel 1 (AtCSC1) was the first plant calcium-permeable TRP to be described and can be activated by hyperosmotic shock. Candida albicans CaPHM7 is one of the sequence homologs of AtCSC1, but its function remains unknown.. We show here that CaPhm7 is localized to the plasma membrane in both the yeast and hyphal cells of C. albicans. C. albicans cells lacking CaPHM7 are sensitive to SDS and ketoconazole but tolerant to rapamycin and zinc. In addition, deletion of CaPHM7 leads to a filamentation defect, reduced colony growth and attenuated virulence in the mouse model of systemic infection.. CaPhm7 is involved in the regulation of ion homeostasis, drug tolerance, filamentation and virulence in this important human fungal pathogen. CaPhm7 could be a potential target of antifungal drugs.

Topics: Animals; Candida albicans; Candidiasis; Disease Models, Animal; Drug Resistance, Fungal; Fungal Proteins; Homeostasis; Hyphae; Ketoconazole; Mice; Sirolimus; Sodium Dodecyl Sulfate; Transient Receptor Potential Channels; Virulence; Zinc

The target of rapamycin complex 1 (TORC1) is the central controller of growth in eukaryotic cells. As one of the downstream targets of TORC1, the protein kinase ScSch9p plays multiple roles in stress resistance, longevity and nutrient sensing in Saccharomyces cerevisiae. In this study, we demonstrate that Candida albicans cells with CaSCH9 deleted have reduced cell sizes and show a delayed log-phase growth. In addition, deletion of CaSCH9 renders C. albicans cells sensitive to rapamycin, caffeine and sodium dodecyl sulfate. Similar to ScSCH9, deletion of CaSCH9 also causes C. albicans cells to become sensitive to cations, but does not lead to a defect in the utilization of galactose. Furthermore, deletion of CaSCH9 affects the filamentation of C. albicans cells and attenuates the virulence in a mouse mode of systemic candidiasis. Therefore, CaSch9p is an important regulator for the cell growth, filamentation and virulence of this human fungal pathogen.

Topics: Animals; Antifungal Agents; Caffeine; Candida albicans; Candidiasis; Fungal Proteins; Galactose; Gene Deletion; Male; Mice; Mice, Inbred BALB C; Protein Kinases; Sirolimus; Sodium Dodecyl Sulfate; Survival Analysis; Virulence; Virulence Factors

The function of GLN3, a GATA factor encoding gene, in nitrogen metabolism of Candida albicans was examined. GLN3 null mutants had reduced growth rates on multiple nitrogen sources. More severe growth defects were observed in mutants lacking both GLN3 and GAT1, a second GATA factor gene. GLN3 was an activator of two genes involved in ammonium assimilation, GDH3, encoding NADP-dependent glutamate dehydrogenase, and MEP2, which encodes an ammonium permease. GAT1 contributed to MEP2 expression, but not that of GDH3. A putative general amino acid permease gene, GAP2, was also activated by both GLN3 and GAT1, but activation by GLN3 was nitrogen source dependent. GLN3 was constitutively expressed, but GAT1 expression varied with nitrogen source and was reduced 2- to 3-fold in gln3 mutants. Both gln3 and gat1 mutants exhibited reduced sensitivity to rapamycin, suggesting they function downstream of TOR kinase. Hyphae formation by gln3 and gat1 mutants differed in relation to nitrogen source. The gln3 mutants formed hyphae on several nitrogen sources, but not ammonium or urea, suggesting a defect in ammonium assimilation. Virulence of gln3 mutants was reduced in a murine model of disseminated disease. We conclude that GLN3 has a broad role in nitrogen metabolism, partially overlapping, but distinct from that of GAT1, and that its function is important for the ability of C. albicans to survive within the host environment.

Topics: Amino Acid Sequence; Animals; Antifungal Agents; Candida albicans; Candidiasis; Drug Resistance, Fungal; Fungal Proteins; GATA Transcription Factors; Gene Deletion; Gene Expression Regulation, Fungal; Glutamate Dehydrogenase (NADP+); Hyphae; Membrane Transport Proteins; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Mutagenesis, Insertional; Nitrogen; Quaternary Ammonium Compounds; Sequence Alignment; Sirolimus; Urea; Virulence

Voriconazole is currently contraindicated for use with sirolimus. We report our experience with voriconazole/sirolimus in two renal transplant recipients. To our knowledge, this is the first experience with voriconazole/sirolimus. An interaction requiring a 75% to 87.5% sirolimus dose reduction was noted, but goal trough levels and clinical tolerability were achieved.

Topics: Adult; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Candidiasis; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases, Fungal; Male; Middle Aged; Postoperative Complications; Pyrimidines; Sirolimus; Triazoles; Voriconazole