Toxicity mechanisms of amphotericin B and its neutralization by conjugation with arabinogalactan

Sarah Kagan, Diana Ickowicz, Miriam Shmuel, Yoram Altschuler, Edward Sionov, Miriam Pitusi, Aryeh Weiss, Shimon Farber, Abraham J. Domb, Itzhack Polacheck

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Amphotericin B (AMB) is an effective antifungal agent. However, its therapeutic use is hampered by its toxicity, mainly due to channel formation across kidney cell membranes and the disruption of postendocytic trafficking. We previously described a safe injectable AMB-arabinogalactan (AG) conjugate with neutralized toxicity. Here we studied the mechanism of the toxicity of free AMB and its neutralization by conjugation with AG. AMB treatment of a kidney cell line modulated the trafficking of three receptors (C-X-C chemokine receptor type 4 [CXCR4], M1 receptor, and human transferrin receptor [hTfnR]) due to an increase in endosomal pH. Similar data were also obtained in yeast but with an increase in vacuolar pH and the perturbation of Hxt2-green fluorescent protein (GFP) trafficking. The conjugation of AMB with AG neutralized all elements of the toxic activity of AMB in mammalian but not in fungal cells. Based on these results, we provide an explanation of how the conjugation of AMB with AG neutralizes its toxicity in mammalian cells and add to the knowledge of the mechanism of action of free AMB in both fungal and mammalian cells.

Original languageEnglish
Pages (from-to)5603-5611
Number of pages9
JournalAntimicrobial Agents and Chemotherapy
Volume56
Issue number11
DOIs
StatePublished - Nov 2012
Externally publishedYes

Fingerprint

Dive into the research topics of 'Toxicity mechanisms of amphotericin B and its neutralization by conjugation with arabinogalactan'. Together they form a unique fingerprint.

Cite this