Potentiation of azole antifungals by 2-adamantanamine.

Abstract

Azoles are among the most successful classes of antifungals. They act by inhibiting α-14 lanosterol demethylase in the ergosterol biosynthesis pathway. Oropharyngeal candidiasis (OPC) occurs in about 90% of HIV-infected individuals, and 4 to 5% are refractory to current therapies, including azoles, due to the formation of resistant biofilms produced in the course of OPC. We reasoned that compounds affecting a different target may potentiate azoles to produce increased killing and an antibiofilm therapeutic. 2-Adamantanamine (AC17) was identified in a screen for compounds potentiating the action of miconazole against biofilms of Candida albicans. AC17, a close structural analog to the antiviral amantadine, did not affect the viability of C. albicans but caused the normally fungistatic azoles to become fungicidal. Transcriptome analysis of cells treated with AC17 revealed that the ergosterol and filamentation pathways were affected. Indeed, cells exposed to AC17 had decreased ergosterol contents and were unable to invade agar. In vivo, the combination of AC17 and fluconazole produced a significant reduction in fungal tissue burden in a guinea pig model of cutaneous candidiasis, while each treatment alone did not have a significant effect. The combination of fluconazole and AC17 also showed improved efficacy (P value of 0.018) compared to fluconazole alone when fungal lesions were evaluated. AC17 is a promising lead in the search for more effective antifungal therapeutics.

• Authors: Michael D Lafleur, Lingmei Sun, Ida Lister, John Keating, Andre Nantel, Lisa Long, Mahmoud Ghannoum, Jeffrey North, Richard E Lee, Ken Coleman, Thomas Dahl, Kim Lewis
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 57 Issue 8 Pg. 3585-92 (Aug 2013) ISSN: 1098-6596 [Electronic] United States
• PMID: 23689724 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antifungal Agents
• Culture Media
• Miconazole
• Fluconazole
• Amantadine
• Ergosterol

Topics

• Amantadine (analogs & derivatives, pharmacology)
• Animals
• Antifungal Agents (chemistry, pharmacology)
• Biofilms (drug effects)
• Candida albicans (chemistry, drug effects, genetics)
• Candidiasis, Cutaneous (drug therapy)
• Culture Media (chemistry)
• Drug Evaluation, Preclinical
• Drug Synergism
• Ergosterol (metabolism)
• Fluconazole (pharmacology)
• Gene Expression Profiling
• Guinea Pigs
• Hep G2 Cells
• Hepatocytes (microbiology)
• Humans
• Miconazole (chemistry, pharmacology)