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|Title:||Hexadecylphosphocholine (Miltefosine) has broad-spectrum fungicidal activity and is efficacious in a mouse model of cryptococcosis|
|Citation:||Antimicrobial Agents and Chemotherapy, 2006; 50(2):414-421|
|Publisher:||Amer Soc Microbiology|
|Fred Widmer, Lesley C. Wright, Daniel Obando, Rosemary Handke, Ranjini Ganendren, David H. Ellis and Tania C. Sorrell|
|Abstract:||The alkyl phosphocholine drug miltefosine is structurally similar to natural substrates of the fungal virulence determinant phospholipase B1 (PLB1), which is a potential drug target. We determined the MICs of miltefosine against key fungal pathogens, correlated antifungal activity with inhibition of the PLB1 activities (PLB, lysophospholipase [LPL], and lysophospholipase-transacylase [LPTA]), and investigated its efficacy in a mouse model of disseminated cryptococcosis. Miltefosine inhibited secreted cryptococcal LPTA activity by 35% at the subhemolytic concentration of 25 μM (10.2 μg/ml) and was inactive against mammalian pancreatic phospholipase A2 (PLA2). At 250 μM, cytosolic PLB, LPL, and LPTA activities were inhibited by 25%, 51%, and 77%, respectively. The MICs at which 90% of isolates were inhibited (MIC90s) against Candida albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, Cryptococcus gattii, Aspergillus fumigatus, Fusarium solani, Scedosporium prolificans, and Scedosporium apiospermum were 2 to 4 μg/ml. The MICs of miltefosine against Candida tropicalis (n = 8) were 2 to 4 μg/ml, those against Aspergillus terreus and Candida parapsilosis were 8 μg/ml (MIC90), and those against Aspergillus flavus (n = 8) were 2 to 16 μg/ml. Miltefosine was fungicidal for C. neoformans, with rates of killing of 2 log units within 4 h at 7.0 μM (2.8 μg/ml). Miltefosine given orally to mice on days 1 to 5 after intravenous infection with C. neoformans delayed the development of illness and mortality and significantly reduced the brain cryptococcal burden. We conclude that miltefosine has broad-spectrum antifungal activity and is active in vivo in a mouse model of disseminated cryptococcosis. The relatively small inhibitory effect on PLB1 enzyme activities at concentrations exceeding the MIC by 2 to 20 times suggests that PLB1 inhibition is not the only mechanism of the antifungal effect.|
|Keywords:||Animals; Mice, Inbred BALB C; Humans; Mice; Fungi; Cryptococcosis; Disease Models, Animal; Hemolysis; Phosphorylcholine; Multienzyme Complexes; Lysophospholipase; Acyltransferases; Enzyme Inhibitors; Antifungal Agents; Microbial Sensitivity Tests; Female|
|Rights:||Copyright © 2006 by the American Society for Microbiology.|
|Appears in Collections:||Molecular and Biomedical Science publications|
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