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 fumigatus to the novel conjugated styryl ketone NC1175 and the results were compared with those obtained for amphotericin B and itraconazole. All 20 clinical isolates of A. fumigatus examined were susceptible to NC1175 (MIC = 5.54 +/- 2.48 mg/L; range 2.92-11.68 mg/L), and the minimum lethal concentration (MLC) was only twice the MIC, suggesting that NC1175 is fungicidal. The mean MIC values of amphotericin B (1.22 +/- 0.58 mg/L; range 0.5-4 mg/L) and itraconazole (0.37 +/- 0.11 mg/L; range 0.125-0.5 mg/L) were approximately nine- and 22-fold, respectively, lower than that of NC1175. Both amphotericin B-resistant (n = 18) and itraconazole-resistant (n = 28) isolates of A. fumigatus were as susceptible to NC1175 as amphotericin B-, and itraconazole-susceptible isolates. Kill curve experiments revealed that NC1175 at 23.35 mg/L (approximately four times the MIC) killed > or = 99% of conidia within 24 h of exposure to the drug. The in-vivo susceptibility of A. fumigatus to NC1175 was investigated using a murine pulmonary aspergillosis model. Treatment of infected mice with amphotericin B or NC1175 did not result in significant improvement of the mean survival (amphotericin B, 7.05 +/- 0.07 days; NC1175, 6.65 +/- 1.25 days) of the animals compared with that of the placebo group (7.21 +/- 1.20 days). However, semiquantitative organ culture revealed that clearance of A. fumigatus occurred in 16.6%, 50% and 66.6% of the mice treated with placebo, NC1175 and amphotericin B, respectively (P value for the control and the treated groups <0.01). These results suggest that NC1175 has in-vivo and in-vitro activity against A. fumigatus and can be used as a prototypic molecule for further development as an antifungal agent.
Manavathu
E K
EK
Department of Medicine, Wayne State University School of Medicine, Wayne State University, Detroit, MI 48201, USA. aa1388@wayne.edu
Dimmock
J R
JR
Vashishtha
S C
SC
Cutright
J
J
Chandrasekar
P H
PH
D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004352:Drug Resistance, Microbial; D005260:Female; D017964:Itraconazole / Q000494:pharmacology; D008172:Lung Diseases, Fungal / Q000188:drug therapy* / Q000382:microbiology; D008352:Mannich Bases / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008811:Mice, Inbred DBA; D008826:Microbial Sensitivity Tests; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000935:Antifungal Agents; D008352:Mannich Bases; C117532:NC 1175; D010880:Piperidines; D017964:Itraconazole; D000666:Amphotericin B