In-vitro and in-vivo susceptibility of Aspergillus fumigatus to a novel conjugated styryl ketone

We investigated the in-vitro and in-vivo susceptibility of Aspergillus fumi gatus to the novel conjugated styryl ketone NC1175 and the results were com pared with those obtained for amphotericin B and itraconazole. All 20 clini cal isolates of A. fumigatus examined were susceptible to NC1175 (MIC = 5.5 4 +/- 2.48 mg/L; range 2.92-11.68 mg/L), and the minimum lethal concentrati on (MLC) was only twice the MIG, suggesting that NC1175 is fungicidal. The mean MIC values of amphotericin B (1.22 +/- 0.58 mg/L; range 0.5-4 mg/L) an d itraconazele (0.37 +/- 0.11 mg/L; range 0.125-0.5 mg/L) were approximatel y nine- and 22-fold, respectively, lower than that of NC1175. Both amphoter icin B-resistant (n = 18) and itraconazole-resistant (n = 28) isolates of A . fumigatus were as susceptible to NC1175 as amphotericin B-, and itraconaz ole-susceptible isolates. Kill curve experiments revealed that NC1175 at 23 .35 mg/L (approximately four times the MIG) killed greater than or equal to 99% of conidia within 24 h of exposure to the drug. The in-vivo susceptibi lity of A. fumigatus to NC1175 was investigated using a murine pulmonary as pergillosis model. Treatment of infected mice with amphotericin B or NC1175 did not result in significant improvement of the mean survival (amphoteric in B, 7.05 +/- 0.07 days; NC1175, 6.65 +/- 1.25 days) of the animals compar ed with that of the placebo group (7.21 +/- 1.20 days). However, semiquanti tative organ culture revealed that clearance of A. fumigatus occurred in 16 .6%, 50% and 66.6% of the mice treated with placebo, NC1175 and amphoterici n B, respectively (P value for the control and the treated groups <0.01). T hese results suggest that NC1175 has in-vivo and in-vitro activity against A. fumigatus and can be used as a prototypic molecule for further developme nt as an antifungal agent.