Drug Discovery: Nature’s Approach

Abstract

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.