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.

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The novel lipopeptide antibiotic A21978C complex is active against Gram-positive organisms. This complex consists of a commonpeptide nucleus with various lipid acyl groups at the iV-terminus characteristic of each individual factor. The fatty acid acyl group is removed by incubation of the A21978Ccomplex with Actinoplanes utahensis to give the peptide nucleus. This peptide nucleus has the same amino acid sequence as A21978C. New analogs of A21978Cwere synthesized by acylation of the iV-terminus of a ter/-butoxycarbonyl (ter/-BOC)-protected nucleus and subsequent deprotection. XHNMRshowed that the newly introduced acyl group was at the desired iV-terminus. Three major groups of analogs were synthesized bearing fatty acid acyl, amino-aroyl and extended peptide side chains. Each analog was evaluated for antimicrobial activity and acute toxicity. Of these analogs, the «-decanoyl analog of A21978C(LY146032) gave the best survival in the mouse acute toxicity test at a high dose of 1,000 mg/kg, iv and was chosen for further study. This analog has been named daptomycin.

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