Evaluation of Nikkomycins X and Z in murine models of coccidioidomycosis, histoplasmosis, and blastomycosis

R. F. Hector, B. L. Zimmer, Demosthenes Pappagianis

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)587-593
Number of pages7
JournalAntimicrobial Agents and Chemotherapy
Volume34
Issue number4
StatePublished - 1990

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Blastomycosis
Coccidioidomycosis
Histoplasmosis
Coccidioides
Fungi
Chitin Synthase
Blastomyces
Azoles
Aspergillus fumigatus
Transmission Electron Microscopy
Intravenous Infusions
Toxicology
Cell Wall
Oral Administration
nikkomycin X
nikkomycin
Pharmacokinetics
Yeasts
In Vitro Techniques

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Evaluation of Nikkomycins X and Z in murine models of coccidioidomycosis, histoplasmosis, and blastomycosis. / Hector, R. F.; Zimmer, B. L.; Pappagianis, Demosthenes.

In: Antimicrobial Agents and Chemotherapy, Vol. 34, No. 4, 1990, p. 587-593.

Research output: Contribution to journalArticle

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