Correlation of cilofungin in vivo efficacy with its activity against Aspergillus fumigatus (1,3)‐β‐d‐glucan synthase

(1,3)‐β‐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 μg/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 α‐amylase. Enzyme activity in crude membrane preparations was measured in the presence of several antifungal agents. Enzyme inhibition results showed that 1 μg/ml of papulacandin B, echinochandin B, aculeacin A and cilofungin all inhibited A. fumigatus glucan synthase activity (40–71%) while 1 μg/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.