HIV positive patients suffering AIDS manifest a host of symptoms characteristic of impaired immuno-competency including susceptibility to opportunistic fungal infections. Mycoses such as candidiasis, histoplasmosis and cryptococcosis are frequently invasive in these cases and have been routinely treated with intravenous amphotericin B. The mechanism of action of amphotericin B involves selective membrane disruption of yeast cells, however, the high toxicity of the polyene macrolides is problematic in AIDS patient treatment; less toxic antifungals with the same mechanism of action are clearly needed. Marine invertebrates such as sponges, tunicates and molluscs are natural sources of diverse new natural products, some with antifungal properties. A few antibiotics from marine zoanthids (phylum Cnidaria, Subclass Zoantharia, order Zoanthidae) have been reported, however, zoanthids have not been systematically investigated for antifungal compounds, despite the indication of compounds with high biological activity such as palytoxin. It is proposed, herein, to 1. Systematically survey temperate and tropical marine zoanthids and sponges for antifungal organic compounds employing a mechanisms selective assay developed in our laboratories. 2. Isolate, purify and chemically characterize new antifungal compounds as potential leads to chemotherapeutics with utility in treatment of opportunistic systemic mycoses in immunocompromised patients. 3. Compare the activity and mechanisms of action of new antifungals with amphotericin B to identify new fungicidal agents. 4. Determine the structures, especially absolute configuration, of new antifungal agents using spectroscopic techniques. 5. Evaluate compounds, identified from the mechanism-selective screen as membrane active, for in vitro anti-HIV activity. Zoanthids and co-occurring invertebrates will be collected, extracted and assayed for antifungal activity. Active extracts will be separated using a bioassay guided fractionation and the antifungal compounds isolated, purified and characterized. Structures of new antifungals will be determined by spectroscopic techniques. The mechanisms of activity of new compounds will be briefly examined by a novel assay which compares the mode of action with that of amphotericin B to identify compounds with similar modes of action. This will aid in the identification of new modes of antifungal activity and also identify those compounds which selectively bind to sterol, the basis of amphotericin B activity. Because the latter is also responsible for the novel anti-HIV activity of amphotericin B methyl ester, this work may uncover new agents which inhibit HIV replication.
| Nicholas, G M; Hong, T W; Molinski, T F et al. (1999) Oceanapiside, an antifungal bis-alpha,omega-amino alcohol glycoside from the marine sponge Oceanapia phillipensis. J Nat Prod 62:1678-81 |
| Shafer, C M; Molinski, T F (1998) Practical synthesis of 2,6-dideoxy-D-lyxo-hexose (""2-deoxy-D-fucose"") from D-galactose. Carbohydr Res 310:223-8 |
| Franklin, M A; Penn, S G; Lebrilla, C B et al. (1996) Bastadin 20 and bastadin O-sulfate esters from Ianthella basta: novel modulators of the Ry1R FKBP12 receptor complex. J Nat Prod 59:1121-7 |
| Searle, P A; Molinski, T F (1995) 4-Dehydroecdysterone, a new ecdysteroid from the zoanthid Parazoanthus sp. J Nat Prod 58:264-8 |
| Antonio, J; Molinski, T F (1993) Screening of marine invertebrates for the presence of ergosterol-sensitive antifungal compounds. J Nat Prod 56:54-61 |
