Antifungal Properties of 2-adamantanamine, a Potentiator of Azole Antifungals

Ref ID: 18743

Author:

M. LaFleur, PhD (Doctor of Philosophy) – Senior Manager1,2, L. Long, MS – Veterinary Technician 3, M. Ghannoum, PhD – Professor 3, J. North, PhD – Postdoctoral Associate 4, R. Lee, PhD – Professor 4, K. Lewis, PhD – Professor 2;

Author address:

1Arietis Corp., Boston, MA, 2Northeastern Univ., Boston, MA, 3Case Western Reserve Univ., Cleveland, OH, 4St. Jude Children’s Res. Hosp., Memphis, TN.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: 90% of HIV infected individuals will develop oral candidiasis and refractory infection occurs in 4-5% of patients. Oral candidiasis is treated with azoles, but these drugs are static and do not provide a long-term cure. We identified 2-adamantanamine (AC17) in a screen for potentiators of the azole drugs. Methods: Time kill synergy tests were performed with Candida albicans strain SC5314, diluted into RPMI 1640 medium and exposed to AC17 and antifungals for 24-48 hours. Agar diffusion susceptibility tests were performed with and without 10 µg/mL of AC17 and invasion assay were performed on Spider agar. Pharmacokinetic studies were performed in mice dosed with 100 mg/kg AC17 and drug plasma quantification was performed by LC/MS. Microarray studies were performed on cells exposed to 100 µg/mL of AC17 for 3 hours. Efficacy studies were performed using a guinea pig model of cutaneous candidiasis and antifungals were applied topically, once daily. Results: AC17 had no effect on viability of Candida albicans, but it caused the fungistatic agents, fluconazole and voriconazole, to become fungicidal in time kill and agar diffusion assays. AC17 also prevented invasion and hyphal elongation, two key events in Candida pathogenesis. AC17 exhibited excellent drug-like pharmacokinetic properties and synergy with the azoles was achieved at very low systemic concentrations. Microarray studies, suggested that AC17 targets the cell membrane and does not act through inhibition of calcineurin or HSP90. The combination of AC17 and fluconazole improved efficacy in a guinea pig model of cutaneous candidiasis. Conclusions: AC17 synergized with the azole, suggesting an opportunity to develop improved therapeutics to treat candidiasis.

Abstract Number: F-815

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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