Polyoxins and nikkomycins: progress in synthetic and biological studies.

Polyoxins and nikkomycins are naturally-occurring peptidyl nucleoside antibiotics. As inhibitors of chitin synthetase, they exhibit antifungal activity, but lack antibacterial activity. Since they also lack mammalian toxicity, they represent potentially useful models for the development of effective agents for the treatment of opportunistic fungal infections. Direct clinical application of the natural peptidyl nucleosides is compromised by their attenuated in vivo activity, apparently due to their hydrolytic lability and inefficient fungal cell wall permeability. Thus, extensive efforts have focused on syntheses of natural peptidyl nucleosides, their components and analogs in anticipation of establishing useful structure-activity-relationships (SAR) for the development of new antifungal agents. A comprehensive and critical review of the synthetic effort and subsequent biological studies reveals that while much has been accomplished, ideal antifungal agents have not yet been developed from the natural peptidyl nucleoside leads. The need for continued study of agents with novel modes of action is emphasized by the realization that other structurally varied antifungal agents currently used clinically have limitations and often severe side effects, including nephrotoxicity.