Antifungal Activities of Rapamycin and Its Derivatives, Prolylrapamycin, 32-Desmethylrapamycin, and 32-Desmethoxyrapamycin.

Wong, Grace K.; Griffith, Stephen M.; Kojima, Ikuo; Demain, Arnold L.

doi:10.7164/antibiotics.51.487

Cited by 45 publications

(30 citation statements)

References 7 publications

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“…Of particular interest are the invariably conserved residues within the hydrophobic pocket of the FRB domain that are critical for rapamycin binding to Tor (5,7,34,47,52,59). This observation is in agreement with previous studies showing that rapamycin has broad-spectrum antifungal activity against several human pathogens, including Candida albicans and Cryptococcus neoformans, and that its activity in these species is mediated by conserved rapamycin-FKBP12 drugprotein complexes (1,13,15,17,56,58).…”

Section: Discussionsupporting

confidence: 82%

“…Rapamycin was first identified as an antimicrobial with potent activity against Candida albicans (1,56). Subsequently, rapamycin was shown to have robust antifungal activity against several human fungal pathogens, such as Cryptococcus neoformans, Aspergillus fumigatus, Fusarium oxysporum, and several pathogenic Penicillium species (13,58), and it was later found to have potent immunosuppressive activity (35). In yeast and mammalian cells, rapamycin inhibits Tor through its association with the prolyl isomerase FKBP12, forming a binary complex that binds to the highly conserved FRB (FKBP12-rapamycin binding) domain of Tor.…”

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confidence: 99%

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Rapamycin Exerts Antifungal Activity In Vitro and In Vivo against Mucor circinelloides via FKBP12-Dependent Inhibition of Tor

et al. 2012

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The zygomycete Mucor circinelloides is an opportunistic fungal pathogen that commonly infects patients with malignancies, diabetes mellitus, and solid organ transplants. Despite the widespread use of antifungal therapy in the management of zygomycosis, the incidence of infections continues to rise among immunocompromised individuals. In this study, we established that the target and mechanism of antifungal action of the immunosuppressant rapamycin in M. circinelloides are mediated via conserved complexes with FKBP12 and a Tor homolog. We found that spontaneous mutations that disrupted conserved residues in FKBP12 conferred rapamycin and FK506 resistance.

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Section: Discussionsupporting

confidence: 82%

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confidence: 99%

Rapamycin Exerts Antifungal Activity In Vitro and In Vivo against Mucor circinelloides via FKBP12-Dependent Inhibition of Tor

et al. 2012

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“…Third, while rapamycin itself is unlikely to be of clinical benefit in fungal infection, because immunosuppression predisposes individuals to cryptococcal meningitis, a collection of nonimmunosuppressive rapamycin analogs are available. Fourth, rapamycin has broad-spectrum antifungal activity against several human pathogens, including C. albicans, C. neoformans, and A. fumigatus (48,73).…”

Section: Discussionmentioning

confidence: 99%

Rapamycin Antifungal Action Is Mediated via Conserved Complexes with FKBP12 and TOR Kinase Homologs inCryptococcus neoformans

Cruz¹,

Cavallo

Görlach³

et al. 1999

Molecular and Cellular Biology

167

146

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Cryptococcus neoformans is a fungal pathogen that causes meningitis in patients immunocompromised by AIDS, chemotherapy, organ transplantation, or high-dose steroids. Current antifungal drug therapies are limited and suffer from toxic side effects and drug resistance. Here, we defined the targets and mechanisms of antifungal action of the immunosuppressant rapamycin in C. neoformans. In the yeast Saccharomyces cerevisiae and in T cells, rapamycin forms complexes with the FKBP12 prolyl isomerase that block cell cycle progression by inhibiting the TOR kinases. We identified the gene encoding a C. neoformans TOR1 homolog. Using a novel two-hybrid screen for rapamycin-dependent TOR-binding proteins, we identified the C. neoformans FKBP12 homolog, encoded by the FRR1 gene. Disruption of the FKBP12 gene conferred rapamycin and FK506 resistance but had no effect on growth, differentiation, or virulence of C. neoformans. Two spontaneous mutations that confer rapamycin resistance alter conserved residues on TOR1 or FKBP12 that are required for FKBP12-rapamycin-TOR1 interactions or FKBP12 stability. Two other spontaneous mutations result from insertion of novel DNA sequences into the FKBP12 gene. Our observations reveal that the antifungal activities of rapamycin and FK506 are mediated via FKBP12 and TOR homologs and that a high proportion of spontaneous mutants in C. neoformans result from insertion of novel DNA sequences, and they suggest that nonimmunosuppressive rapamycin analogs have potential as antifungal agents.Cryptococcus neoformans is an opportunistic fungal pathogen that causes systemic mycosis in immunocompromised patients (20,45). Cryptococcosis in patients with AIDS is characterized by a poor response to therapy and a risk of recurrent disease requiring lifelong suppressive antifungal regimens. Current treatments include amphotericin B, flucytosine, and fluconazole. However, treatment failures and toxicity are common, and new antifungal agents are needed.C. neoformans is sensitive to the immunosuppressants rapamycin, FK506, and cyclosporine (CsA) (48, 49). These compounds are natural products with antifungal activity and are also potent immunosuppressants used to treat graft rejection in transplant recipients (7,38). Rapamycin is a macrolide originally discovered in a screen for antimicrobial activity against Candida albicans and later found to have potent immunosuppressive activity (62).Rapamycin, FK506, and CsA suppress the immune system by inhibiting signal transduction steps required for T-cell activation (for reviews, see references 19 and 59). The mechanisms of action of these compounds have been studied in lymphocytes and Sacharomyces cerevisiae (for reviews, see references 11, 18, 32, and 59). These hydrophobic compounds diffuse into the cell and bind intracellular receptors known as immunophilins. The immunophilins are ubiquitous and conserved from yeast to humans. FK506 and rapamycin bind the immunophilin FKBP12, whereas CsA binds cyclophilin A. Although the cyclophilin and FKBP proteins have no s...

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“…This agent exhibits multiple mechanisms of action other than antiinflammatory property. It also exhibits anti-angiogenic, antifibrotic, antifungal, and antimigratory mechanisms (12,(16)(17)(18)(19). Rapamycin decreases VEGF production and alters the response of endothelial cells to VEGF stimulation (12).…”

Section: Introductionmentioning

confidence: 99%

Nanomicellar Topical Aqueous Drop Formulation of Rapamycin for Back-of-the-Eye Delivery

et al. 2014

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Abstract. The objective of this study was to develop a clear, aqueous rapamycin-loaded mixed nanomicellar formulations (MNFs) for the back-of-the-eye delivery. MNF of rapamycin (0.2%) was prepared with vitamin E tocopherol polyethylene glycol succinate (TPGS) (Vit E TPGS) and octoxynol-40 (Oc-40) as polymeric matrix. MNF was characterized by various parameters such as size, charge, shape, and viscosity. Proton nuclear magnetic resonance ( 1 H NMR) was used to identify unentrapped rapamycin in MNF. Cytotoxicity was evaluated in human retinal pigment epithelial (D407) and rabbit primary corneal epithelial cells (rPCECs). In vivo posterior ocular rapamycin distribution studies were conducted in male New Zealand white rabbits. The optimized MNF has excellent rapamycin entrapment and loading efficiency. The average size of MNF was 10.98±0.089 and 10.84±0.11 nm for blank and rapamycin-loaded MNF, respectively. TEM analysis revealed that nanomicelles are spherical in shape. Absence of free rapamycin in the MNF was confirmed by 1 H NMR studies. Neither placebo nor rapamycin-loaded MNF produced cytotoxicity on D407 and rPCECs indicating formulations are tolerable. In vivo studies demonstrated a very high rapamycin concentration in retina-choroid (362.35±56.17 ng/g tissue). No drug was identified in the vitreous humor indicating the sequestration of rapamycin in lipoidal retinal tissues. In summary, a clear, aqueous MNF comprising of Vit E TPGS and Oc-40 loaded with rapamycin was successfully developed. Back-of-the-eye tissue distribution studies demonstrated a very high rapamycin levels in retina-choroid (place of drug action) with a negligible drug partitioning into vitreous humor.

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Antifungal Activities of Rapamycin and Its Derivatives, Prolylrapamycin, 32-Desmethylrapamycin, and 32-Desmethoxyrapamycin.

Cited by 45 publications

References 7 publications

Rapamycin Exerts Antifungal Activity In Vitro and In Vivo against Mucor circinelloides via FKBP12-Dependent Inhibition of Tor

Rapamycin Exerts Antifungal Activity In Vitro and In Vivo against Mucor circinelloides via FKBP12-Dependent Inhibition of Tor

Rapamycin Antifungal Action Is Mediated via Conserved Complexes with FKBP12 and TOR Kinase Homologs inCryptococcus neoformans

Nanomicellar Topical Aqueous Drop Formulation of Rapamycin for Back-of-the-Eye Delivery

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