Manuel Debono

Anti-Candida activity and toxicology of LY121019, a novel semisynthetic polypeptide antifungal antibiotic.

There is an increasing medical need for safe and effective antifungal agents. This need is particularly great in immunocompromised patients that are at risk to infection by the opportunistic pathogen Candida. The treatment of disseminated Candida infections with currently available antifungal agents is not entirely satisfactory because of low efficacy and severe toxicity. A large number of naturally occurring and synthetic compounds of diverse chemical types have been found to inhibit growth and reproduction of pathogenic fungi. An agent with high toxicity for a selective fungal target not shared by mammalian cells offers the potential of treating fungal infections of man with low toxicity. Discovering antifungal agents with selective toxicity for the fungal cell and not other eukaryotic cells, however, has been a major limitation for developing new antifungal agents without serious adverse effects. We will review the in vitro anti-Candida activity of LY121019 (FIG. 1) and the effectiveness of this novel antifungal antibiotic against experimental Candida infections. We will discuss the mode of action of LY121019 based on previous observations that LY121019 caused severe damage to the Candida cell wall and summarize results of toxicological studies on LY 121019.

Drug discovery: nature's approach.

The emergence of immune deficiency diseases, such as AIDS or those that arise from the use of antitumor and organ transplantation regimens, has resulted in major increases in serious fungal infections. Amphotericin B remains the standard treatment of systemic mycoses, but its use is limited by severe toxic properties which make it imperative that safer and more effective therapies be found. Natural products, especially antibiotics from fermentation sources, have played a key role in the search for therapeutically useful drugs. Microorganisms such as the actinomycetes, isolated and cultured from the soil, have provided many useful antimicrobial agents with a wide spectrum of action. However, only a small number of antifungal agents have been discovered using these techniques. This is attributed to the difficulty of finding compounds that are selectively toxic to the eukaryotic fungal cell without causing damage to mammalian cells. Herein we will cover some of the current research in the discovery and evaluation of new antifungal agents from natural sources, and also the current methodology used in their biological evaluation as potential clinical candidates. In addition, a survey of recent natural products with antimycotic activity obtained from both soil screening and marine sources is included. Though not covered in this report, there has been recent interest in higher plants as sources of new structural prototypes for antifungal agents (CClark et al. 1987). Although the soil screen remains a major route for the discovery of new antifungal agents, intensive efforts have been undertaken to develop new methods for screening based upon mode of action. These mechanism-based tests may provide important alternatives to the more direct but capricious screen based on broth or agar dilution.

Review: Anti-infectives Echinocandin lipopeptide antifungal agents: New agents and recent chemical modification studies

The search for new and effective antifungal agents has been intensified by the increase in the incidence of opportunistic infections due to immunological diseases and aggressive immunosuppressive chemotherapy. Natural products have provided several novel leads in this field. Of these the echinocandin lipopeptides are of special interest due to their fungicidal properties and low toxicity. Their mode of action uniquely targets fungal cell wall biosynthesis by inhibiting the production of β-(1,3)-D-glucan, an essential cell wall component. Echinocandin B (ECB) consists of a cyclic hexapeptide whose N-terminus is acylated with linoleic acid. Other natural products of this class have closely related structures with some modification of the cyclic peptide and/or the N-acyl fatty acid chain. Although these natural products share excellent antifungal activity, especially against Candida albicans, and low toxicity, further improvements in therapeutic and solubility properties were sought through chemical modifica...

Isolation and characterization of 4-epi-vancosamine

Abstract Methanolysis of glycopeptides from the A82846 complex with 1.5 N HCl in methanol gives the 2,3,6-trideoxy amino sugar 4- epi -vancosamine, 1 ; this is the first isolation of 1 from a natural product. The structure elucidation is based on NMR studies of the N , O -dibenzoyl methyl glycoside anomers 2 and 3 .

The Fungal Cell Wall — A Target For Lipopeptide Antifungal Agents

There are two key factors that justify the search for safer and more effective antifungal agents for human medicine. First, the currently available antifungal therapy, especially for life-threatening disseminated fungal infections, is not satisfactory because of limited efficacy and/or toxicity (Graybill, 1989). Second, there is an increased incidence of fungal infections attributed to the aggressive use of cancer chemotherapy, organ transplantation, and opportunistic infections associated with acquired immunodeficiency syndrome (AIDS) patients (Patterson and Andriole, 1989).

The photodimerization of 17β-hydroxy-estra-4,9(10)-dien-3-one

The irradiation of 17β-hydroxy-estra-4,9(10)-dien-3-one with ultraviolet light at 3550 A resulted in a dimeric product. Structural information has shown that dimerization occurred across the α,β-olefinic bond. The structure of the dimer is discussed.