sirolimus and geldanamycin

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

Many bacteria and fungi produce natural products that are toxic to other microorganisms and have a variety of physiological effects in animals. Recent studies have revealed that, in several cases, the targets of these agents are components of conserved signal-transduction cascades. This article looks at the mechanisms of action of five natural products--the immunosuppressants cyclosporin A, FK506 and rapamycin, and the antiproliferative agents wortmannin and geldanamycin. These mechanisms reveal the importance of signal-transduction cascades as targets for therapeutic intervention and the enormous utility of studies of natural-product action in simple model genetic systems.

Topics: Androstadienes; Animals; Apoptosis; Benzoquinones; Calcineurin; Cell Cycle; Cyclosporine; Enzyme Inhibitors; Fungi; HSP90 Heat-Shock Proteins; Humans; Immunosuppressive Agents; Lactams, Macrocyclic; Protein Biosynthesis; Quinones; Signal Transduction; Sirolimus; Tacrolimus; Wortmannin

Lafora disease (LD), a fatal genetic form of myoclonic epilepsy, is characterized by abnormally high levels of cellular glycogen and its accumulation as Lafora bodies in affected tissues. Therefore the two defective proteins in LD-laforin phosphatase and malin ubiquitin ligase-are believed to be involved in glycogen metabolism. We earlier demonstrated that laforin and malin negatively regulate cellular glucose uptake by preventing plasma membrane targeting of glucose transporters. We show here that loss of laforin results in activation of serum/glucocorticoid-induced kinase 1 (SGK1) in cellular and animals models and that inhibition of SGK1 in laforin-deficient cells reduces the level of plasma membrane-bound glucose transporter, glucose uptake, and the consequent glycogen accumulation. We also provide evidence to suggest that mammalian target of rapamycin (mTOR) activates SGK1 kinase in laforin-deficient cells. The mTOR activation appears to be a glucose-dependent event, and overexpression of dominant-negative SGK1 suppresses mTOR activation, suggesting the existence of a feedforward loop between SGK1 and mTOR. Our findings indicate that inhibition of SGK1 activity could be an effective therapeutic approach to suppress glycogen accumulation, inhibit mTOR activity, and rescue autophagy defects in LD.

Topics: Animals; Autophagy; Benzoquinones; Biological Transport; Cell Line; Chlorocebus aethiops; COS Cells; Dual-Specificity Phosphatases; Enzyme Inhibitors; Glucose; Glucose Transporter Type 1; Glycogen; Immediate-Early Proteins; Immunosuppressive Agents; Lactams, Macrocyclic; Lafora Disease; Mice; Mice, Knockout; Phosphorylation; Protein Serine-Threonine Kinases; Protein Tyrosine Phosphatases, Non-Receptor; RNA Interference; RNA, Small Interfering; Sirolimus; TOR Serine-Threonine Kinases; Ubiquitin-Protein Ligases