Nikkomycins X and Z, competitive inhibitors of fungal
chitin synthase, were evaluated as therapeutic agents in vitro and in mouse models of
coccidioidomycosis,
histoplasmosis, and
blastomycosis. In vitro, the nikkomycins were found to be most effective against the highly chitinous, dimorphic fungi Coccidioides immitis and Blastomyces dermatitidis, were less effective against yeasts, and were virtually without effect on the filamentous fungus Aspergillus fumigatus. Additionally, by transmission electron microscopy,
nikkomycin Z was highly disruptive to the cell wall and internal structure of the spherule-endospore phase of C. immitis in vitro. In vivo,
nikkomycin Z was more effective than
nikkomycin X, was also found to be superior on a milligram per milligram basis to the majority of
azoles tested in the models of
coccidioidomycosis and
blastomycosis, and was moderately effective in
histoplasmosis. A study of the pharmacokinetics in mice showed that
nikkomycin Z was rapidly eliminated after
intravenous infusion but that absorption after
oral administration was sufficiently slow to allow inhibitory levels to persist for more than 2 h. Results of limited toxicology tests suggest that
nikkomycin Z was well tolerated at the dosages employed.