Hexadecylphosphocholine (Miltefosine) Has Broad-Spectrum Fungicidal Activity and Is Efficacious in a Mouse Model of Cryptococcosis
| Autor: | Lesley C. Wright, Tania C. Sorrell, Fred Widmer, Ranjini Ganendren, Daniel Obando, Rosemary Handke, David Ellis |
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| Rok vydání: | 2006 |
| Předmět: |
Antifungal Agents
Phosphorylcholine Microbial Sensitivity Tests Candida parapsilosis Hemolysis Microbiology Candida tropicalis Mice Multienzyme Complexes Candida krusei medicine Animals Humans Experimental Therapeutics Pharmacology (medical) Enzyme Inhibitors Candida albicans Pharmacology Cryptococcus neoformans Mice Inbred BALB C Miltefosine biology Candida glabrata Scedosporium prolificans Fungi Cryptococcosis biology.organism_classification Disease Models Animal Infectious Diseases Female Lysophospholipase Acyltransferases medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 50:414-421 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.50.2.414-421.2006 |
| Popis: | 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 (PLA 2 ). 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 (MIC 90 s) 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 (MIC 90 ), 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. |
| Databáze: | OpenAIRE |
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