ArticleAntimicrobial agents and chemotherapy2006
Hexadecylphosphocholine (miltefosine) has broad-spectrum fungicidal activity and is efficacious in a mouse model of cryptococcosis.
Article in Antimicrobial agents and chemotherapy, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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44 citing papers in PubMed, 148 citations in OpenAlex.
- Induction Treatment for HIV-Associated Cryptococcal Meningitis: Where Have We Been and Where Are We Going?Microorganisms · 2025Review
- Progress in antileishmanial drugs: Mechanisms, challenges, and prospects.PLoS neglected tropical diseases · 2025Review
- Synthesis of Keratin Nanoparticles Extracted from Human Hair through Hydrolysis with Concentrated Sulfuric Acid: Characterization and Cytotoxicity.Materials (Basel, Switzerland) · 2024Article
- Strategies of Pharmacological Repositioning for the Treatment of Medically Relevant Mycoses.Infection and drug resistance · 2024Review
- Miltefosine: A Repurposing Drug against Mucorales Pathogens.Journal of fungi (Basel, Switzerland) · 2023Article
- Phospholipase B Is Critical for Cryptococcus neoformans Survival in the Central Nervous System.mBio · 2023Article
- Oral delivery of brain-targeted miltefosine-loaded alginate nanoparticles functionalized with polysorbate 80 for the treatment of cryptococcal meningitis.The Journal of antimicrobial chemotherapy · 2023Article
- Review
- Review
- Invasive candidiasis: investigational drugs in the clinical development pipeline and mechanisms of action.Expert opinion on investigational drugs · 2022Article
- In Vitro Antifungal Susceptibility Profile of Miltefosine against a Collection of Azole and Echinocandins ResistantJournal of fungi (Basel, Switzerland) · 2022Article
- A functional genomic screen in Saccharomyces cerevisiae reveals divergent mechanisms of resistance to different alkylphosphocholine chemotherapeutic agents.G3 (Bethesda, Md.) · 2021Article
- Article
- Miltefosine AgainstFrontiers in cellular and infection microbiology · 2021Article
- New Approaches for Cryptococcosis Treatment.Microorganisms · 2020Review
- Article
- Antifungal Activity and Mode of Action of Miltefosine Against Clinical Isolates ofFrontiers in microbiology · 2020Article
- Reviewing the Effects of Miltefosine and Suggesting It for the Treatment of Coronavirus Disease (COVID-19).Infectious diseases · 2020Review
- Miltefosine treatment reduces visceral hypersensitivity in a rat model for irritable bowel syndrome via multiple mechanisms.Scientific reports · 2019Article
- Efficacy of Azithromycin and Miltefosine in Experimental Systemic Pythiosis in Immunosuppressed Mice.Antimicrobial agents and chemotherapy · 2019Article
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7 authors at 3 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
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 microM (10.2 microg/ml) and was inactive against mammalian pancreatic phospholipase A2 (PLA2). At 250 microM, 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 microg/ml. The MICs of miltefosine against Candida tropicalis (n = 8) were 2 to 4 microg/ml, those against Aspergillus terreus and Candida parapsilosis were 8 microg/ml (MIC90), and those against Aspergillus flavus (n = 8) were 2 to 16 microg/ml. Miltefosine was fungicidal for C. neoformans, with rates of killing of 2 log units within 4 h at 7.0 microM (2.8 microg/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.
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