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https://hdl.handle.net/2440/23985
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Type: | Journal article |
Title: | Hexadecylphosphocholine (Miltefosine) has broad-spectrum fungicidal activity and is efficacious in a mouse model of cryptococcosis |
Author: | Widmer, F. Wright, L. Obando, D. Handke, R. Ganendren, R. Ellis, D. Sorrell, T. |
Citation: | Antimicrobial Agents and Chemotherapy, 2006; 50(2):414-421 |
Publisher: | Amer Soc Microbiology |
Issue Date: | 2006 |
ISSN: | 0066-4804 1098-6596 |
Statement of Responsibility: | 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. |
DOI: | 10.1128/AAC.50.2.414-421.2006 |
Published version: | http://aac.asm.org/content/50/2/414.full |
Appears in Collections: | Aurora harvest 6 Molecular and Biomedical Science publications |
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