Enhancing Effects on Vacuole-Targeting Fungicidal Activity of Amphotericin B

Akira Ogita,Toshio Tanaka,Ken-Ichi Fujita

doi:10.3389/fmicb.2012.00100

Abstract

Invasive fungal infections are major threats for immunocompromised patients as well as for those undergoing cancer chemotherapy. Amphotericin B (AmB), a classical antifungal drug with a polyene macrolide structure, is widely used for the control of serious fungal infections. However, the clinical use of this antifungal drug is limited by its side effects and the emergence of drug-resistant strains. AmB lethality has been generally attributed to alterations in plasma membrane ion permeability due to its specific binding to plasma membrane ergosterol. Recent studies with Saccharomyces cerevisiae and Candida albicans reveal the vacuole disruptive action as another cause of AmB lethality on the basis of marked amplification of its activity in combination with allicin, an allyl-sulfur compound from garlic. The enhancing effect of allicin is dependent on the inhibition of ergosterol-trafficking from the plasma membrane to the vacuole membrane, which is considered to be a cellular response to protect against disintegration of the vacuole membrane. The polyol macrolide niphimycin (NM) also possesses vacuole-targeting fungicidal activity, which is greater than that of AmB and nystatin. The alkyl side chain attached to the macrolide ring of NM is considered to possess an allicin-like inhibitory effect on the intracellular trafficking of ergosterol. The vacuole-targeting fungicidal activity was additionally detected with a bactericidal cyclic peptide polymyxin B (PMB), and was markedly enhanced when administered together with allicin, monensin, or salinomycin. The synergistic fungicidal activities of AmB and allicin may have significant implications for the development of vacuole-targeting chemotherapy against fungal infections.

Highlights

The polyene macrolide antibiotic amphotericin B (AmB; Figure 1A) was introduced in the mid-1950s as the first effective antifungal drug for treating systemic mycoses (Johnson and Einstein, 2007)
Vacuole membrane fragmentation is observed concurrently with AmB-induced cell death when this antibiotic is used at a nonlethal concentration in combination with allicin (Figure 1B), an allyl-sulfur compound derived from garlic (Ogita et al, 2006)
We have reported that the extracellular addition of K+ and Mg2+ could restrict cytotoxicity as well as vacuole membrane fragmentation in S. cerevisiae treated with a lethal concentration of AmB alone (Ogita et al, 2010b)

Summary

Introduction

The polyene macrolide antibiotic amphotericin B (AmB; Figure 1A) was introduced in the mid-1950s as the first effective antifungal drug for treating systemic mycoses (Johnson and Einstein, 2007). Vacuole membrane fragmentation is observed concurrently with AmB-induced cell death when this antibiotic is used at a nonlethal concentration in combination with allicin (Figure 1B), an allyl-sulfur compound derived from garlic (Ogita et al, 2006).

Results

Conclusion