Correlation of cilofungin in vivo efficacy with its activity against Aspergillus fumigatus (1,3)-beta-D-glucan synthase.
(1,3)-beta-D-Glucan synthase is a cell wall synthesis enzyme that is the target of cilofungin, an antifungal agent of the lipopeptide class. Cilofungin's glucan synthase inhibitory activity, MIC, and effective dose 50% in a systemic infection mouse model tend to correlate for Candida albicans. This correlation is not seen in Aspergillus fumigatus. MICs for cilofungin against A. fumigatus were consistently > 125 micrograms/ml while the effective dose 50% in a systemic aspergillosis model was determined to be 20.6 mg/kg. To begin to understand this discrepancy, we examined the A. fumigatus glucan synthase. This cell wall enzyme was prepared and its activity was measured by [14C]-glucose incorporation from UDP-[U-14C]glucose into an acid insoluble polymer formed in the presence of alpha-amylase. Enzyme activity in crude membrane preparations was measured in the presence of several antifungal agents. Enzyme inhibition results showed that 1 microgram/ml of papulacandin B, echinochandin B, aculeacin A and cilofungin all inhibited A. fumigatus glucan synthase activity (40-71%) while 1 microgram/ml of amphotericin B, fluconazole, ketoconazole and nikkomycin did not affect enzyme activity. A correlation was therefore established between the inhibitory effect of cilofungin on the A. fumigatus glucan synthase and the effective dose 50% obtained in a systemic aspergillosis mouse model.
Beaulieu
D
D
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
Tang
J
J
Zeckner
D J
DJ
Parr
T R
TR
D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D001228:Aspergillosis / Q000188:drug therapy*; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D054714:Echinocandins; D015725:Fluconazole / Q000494:pharmacology; D005964:Glucosyltransferases / Q000187:drug effects*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D010456:Peptides, Cyclic / Q000494:pharmacology*; D029702:Schizosaccharomyces pombe Proteins; D013045:Species Specificity; D016019:Survival Analysis
D054714:Echinocandins; D008565:Membrane Proteins; D010456:Peptides, Cyclic; D029702:Schizosaccharomyces pombe Proteins; D000666:Amphotericin B; D015725:Fluconazole; C042101:cilofungin; D005964:Glucosyltransferases; C020570:1,3-beta-glucan synthase