Evaluation of water-soluble pneumocandin analogs L-733560, L-705589, and L-731373 with mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis.
The activities of the water-soluble pneumocandin derivatives L-733560, L-705589, and L-731373 were evaluated in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis and were compared with those of commercially available antifungal agents. Pneumocandins are inhibitors of 1,3-beta-D-glucan synthesis. In the aspergillosis model, L-733560 and L-705589 significantly prolonged the survival of DBA/2N mice challenged intravenously with Aspergillus fumigatus conidia. L-733560 and L-705589 exhibited efficacies comparable to that of amphotericin B (AMB) with 90% effective doses of 0.48, 0.12, and 0.36 mg/kg of body weight, respectively. Two mouse models of disseminated candidiasis were used to evaluate these compounds. In both models, mice were challenged intravenously with Candida albicans. In a C. albicans survival model with DBA/2N and CD-1 mice, the efficacy of L-733560 was comparable to that of AMB, while L-731373 and L-705589 were somewhat less active. In a previously described C. albicans target organ kidney assay, the pneumocandin analogs and AMB at doses of > or = 0.09 mg/kg were effective in sterilizing kidneys, while fluconazole and ketoconazole were considerably less active and did not sterilize kidneys when they were used at concentrations of < or = 100 mg/kg. Although orally administered L-733560 showed activity in both candidiasis models, its efficacy was reduced compared with that of parenterally administered drug. In a disseminated cryptococcosis mouse model that measures the number of CFU of Cryptococcus neoformans per gram of brain and spleen, L-733560 at 10 mg/kg was ineffective in reducing the counts in organs, while AMB at 0.31 mg/kg sterilized the organs. These results indicate that the pneumocandins may be beneficial as potent parenterally administered therapeutic agents for disseminated aspergillosis and candidiasis.
Abruzzo
G K
GK
Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA.
Flattery
A M
AM
Gill
C J
CJ
Kong
L
L
Smith
J G
JG
Krupa
D
D
Pikounis
V B
VB
Kropp
H
H
Bartizal
K
K
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D000935:Antifungal Agents / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D003453:Cryptococcosis / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D051379:Mice; D008811:Mice, Inbred DBA; D010455:Peptides; D010456:Peptides, Cyclic / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; C094855:L 705589; C094857:L 731373; C089367:L 733560; D010455:Peptides; D010456:Peptides, Cyclic