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

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.Several antifungal compounds in use today affect the integrity of the fungal cytoplasmic membrane or the synthesis of its constituent ergosterol. Although some of these drugs have demonstrable efficacies and have been widely utilized for treatment of human patients and animals, there is a clear need for drugs with greater fungicidal activities. Because the cell walls of most medically important fungi contain chitin, a polymer not encountered in mammals, compounds which interfere with the synthesis or degradation of this polymer could be useful in therapy of mycoses (3). The polyoxins, which are specific inhibitors of fungal chitin synthase due to their similarity in structure to UDP-N-acetylglucosamine (reviewed in references 4 and 13), the substrate of chitin synthase, had previously been used in vitro against Candida spp. (1, 22, 31) and dimorphic fungi with some success (6,17). A related group of compounds is the nikkomycins, which are structurally similar to the polyoxins and are also inhibitors of chitin synthase (3, 7). We employed nikkomycins X and Z (NX and NZ, respectively) in vitro against selected medically important fungi representing true yeast, dimorphic, and filamentous groups. Because of the high level of activity of these agents against the dimorphic pathogenic fungi, we subsequently evaluated them in mouse models of coccidioidomycosis, blastomycosis, and histoplasmosis, and the results are reported herein. In addition, data are provided on the pharmacokinetics and safety of these compounds.

Recent Advances in Our Understanding of the Environmental, Epidemiological, Immunological, and Clinical Dimensions of Coccidioidomycosis

“…Nikkomycin Z is a novel orphan antifungal drug that inhibits chitin synthase and offers a different mechanism of action from those of currently available antifungal drugs. Based on studies in mice, nikkomycin Z exhibits fungicidal activity and greater efficacy than that of fluconazole (202). In phase I studies, nikkomycin Z achieved clinically relevant concentrations after oral administration, and thus far it has shown no safety concerns (203,204).…”

Compounds active against cell walls of medically important fungi

“…They found that, while polyoxin D offered no protection in comparison with controls, a combination of nikkomycins X and Z was able to delay though not prevent deaths. In contrast, Hector et al found nikkomycins X and Z to be highly efficacious in mouse models of coccidioidomycosis and blastomycosis and moderately efficacious against histoplasmosis (112). When given orally, the compounds were able to completely prevent deaths in mice infected with a 100% lethal challenge, though nikkomycin Z was found to be considerably more active than nikkomycin X.…”

Evaluation of VT-1161 for Treatment of Coccidioidomycosis in Murine Infection Models

“…Mice were infected intracerebrally according to a previously published model (20,21) for the CNS studies. Briefly, anesthetized mice were inoculated through the calvarium with a target dose of 90 spores in 30 l of saline.…”