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Enhancing effects on vacuole-targeting fungicidal activity of amphotericin B.

Ogita A, Fujita K, Tanaka T - Front Microbiol (2012)

Bottom Line: However, the clinical use of this antifungal drug is limited by its side effects and the emergence of drug-resistant strains.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 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.

View Article: PubMed Central - PubMed

Affiliation: Research Center for Urban Health and Sports, Osaka City University Osaka, Japan.

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.

No MeSH data available.


Related in: MedlinePlus

Structures of amphotericin B (AmB) (A) and allicin (B).
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Figure 1: Structures of amphotericin B (AmB) (A) and allicin (B).

Mentions: 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). AmB has been used for controlling life-threatening systemic fungal infections primarily caused by Candida albicans and Aspergillus fumigatus (Lemke et al., 2005). The susceptibility of fungal cells to AmB absolutely requires the presence of ergosterol in the fungal plasma membrane. Molecular modeling studies indicate that AmB creates aqueous pores consisting of an annulus of eight molecules linked hydrophobically to ergosterol embedded in phospholipid bilayers (Baginski et al., 2006). This type of ion channel structure results in altered plasma membrane permeability and leakage of vital cytoplasmic components, such as K+, ultimately inducing cell death (Kerridge, 1980, 1985). However, AmB-induced lethal effects cannot be simply explained by the disturbance in plasma membrane ion transport function, because the leakage of K+ has various secondary effects. Alonso et al. (1979) reported that AmB is a powerful inhibitor of both protein and ribonucleic acid synthesis in yeast cells at concentrations that do not affect the transport of amino acids or nucleosides. The induction of oxidative stress is also considered as an AmB-induced toxic event in C. albicans cells (Sokol-Anderson et al., 1986). The involvement of additional cytotoxic effects in AmB lethality is supported by the fact that the leakage of K+ is not necessarily accompanied by the loss of cell viability (Chen et al., 1978). Clearly, the exact mechanism of AmB lethality is very complex and has not been completely deciphered.


Enhancing effects on vacuole-targeting fungicidal activity of amphotericin B.

Ogita A, Fujita K, Tanaka T - Front Microbiol (2012)

Structures of amphotericin B (AmB) (A) and allicin (B).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3307023&req=5

Figure 1: Structures of amphotericin B (AmB) (A) and allicin (B).
Mentions: 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). AmB has been used for controlling life-threatening systemic fungal infections primarily caused by Candida albicans and Aspergillus fumigatus (Lemke et al., 2005). The susceptibility of fungal cells to AmB absolutely requires the presence of ergosterol in the fungal plasma membrane. Molecular modeling studies indicate that AmB creates aqueous pores consisting of an annulus of eight molecules linked hydrophobically to ergosterol embedded in phospholipid bilayers (Baginski et al., 2006). This type of ion channel structure results in altered plasma membrane permeability and leakage of vital cytoplasmic components, such as K+, ultimately inducing cell death (Kerridge, 1980, 1985). However, AmB-induced lethal effects cannot be simply explained by the disturbance in plasma membrane ion transport function, because the leakage of K+ has various secondary effects. Alonso et al. (1979) reported that AmB is a powerful inhibitor of both protein and ribonucleic acid synthesis in yeast cells at concentrations that do not affect the transport of amino acids or nucleosides. The induction of oxidative stress is also considered as an AmB-induced toxic event in C. albicans cells (Sokol-Anderson et al., 1986). The involvement of additional cytotoxic effects in AmB lethality is supported by the fact that the leakage of K+ is not necessarily accompanied by the loss of cell viability (Chen et al., 1978). Clearly, the exact mechanism of AmB lethality is very complex and has not been completely deciphered.

Bottom Line: However, the clinical use of this antifungal drug is limited by its side effects and the emergence of drug-resistant strains.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 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.

View Article: PubMed Central - PubMed

Affiliation: Research Center for Urban Health and Sports, Osaka City University Osaka, Japan.

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.

No MeSH data available.


Related in: MedlinePlus