Antibiotics that inhibit fungal cell wall development

Abstract

The discovery of antifungal agents that possess selective toxicity against the eukaryotic fungal cell remains an important scientific challenge. The growing medical need for safe and effective antifungal agents stems from the rapidly increasing population of immunocompromised patients. Although the treatment of fungal infections is progressing steadily, currently available agents act on targets that are also found in mammalian cells. Ideally, a selectively toxic antifungal agent should be developed that interacts with a fungal target not found in other eukaryotic cells. This strategy involves selective inhibition of the biosynthesis of important structural elements in the fungal cell. The fungal cell wall is such a therapeutic target. In addition, antibiotics have been discovered that inhibit the development of the fungal cell. The major targets are glucan synthesis, inhibited by the echinocandin lipopeptides and the papulacandins; chitin synthesis, inhibited by the polyoxins and nikkomycins; and mannan, to which the pradimicins selectively bind. The extensively studied echinocandin lipopeptides are fungicidal agents with low toxicity, and one member, cilofungin--a semisynthetic analogue of echinocandin B--has been tested in the clinic. Newer echinocandins, such as LY303366 and the pneumocandins, have excellent activity against yeasts and Pneumocystis carinii infections in animals and show promise as potential clinical antifungal candidates. Chitin synthase inhibitors have been studied through chemical modification of the polyoxins and nikkomycins but are limited because of unfavorable pharmacokinetics. The pradimicins show the ability to bind mannan and thus exert an antifungal effect. The mode of action of this class of inhibitors is not fully understood, but their unique action may provide a better understanding of mannan as a target.