Amphotericin B Channels in the Bacterial Membrane: Role of Sterol and Temperature

Venegas, Berenice; González–Damián, Javier; Célis, Heliodoro; Ortega‐Blake, Iván

doi:10.1016/s0006-3495(03)74656-6

Cited by 64 publications

(51 citation statements)

References 35 publications

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“…In contrast, when HT-AMB was added to synchronized mature-stage (late trophozoite and schizont) cultures, ring-form parasites that had multiplied successfully invaded and remained inside the RBCs for 12 to 24 h of incubation, indicating that HT-AMB has a greater hemolytic effect against pRBCs than it does against non-pRBCs. It is generally assumed that the permeabilizing effects of AMB are related to its ability to form transmembrane channels, whereas the lytic effect is due to the peroxidative action of AMB at the membrane level (3,14,18). The oxidation of unsaturated fatty acids leads to a change in the membrane, which becomes more sensitive to the osmotic shock induced by channel formation.…”

Section: Discussionmentioning

confidence: 99%

Potent Plasmodicidal Activity of a Heat-Induced Reformulation of Deoxycholate-Amphotericin B (Fungizone) against Plasmodium falciparum

Hatabu

Takada

Taguchi

et al. 2005

Antimicrob Agents Chemother

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The emergence and spread of drug-resistant Plasmodium falciparum continue to pose problems in malaria chemotherapy. Therefore, it is necessary to identify new antimalarial drugs and therapeutic strategies. In the present study, the activity of a heat-treated form of amphotericin B (HT-AMB) against P. falciparum was evaluated. The efficacy and toxicity of HT-AMB were also compared with those of the standard formulation (AMB). HT-AMB showed significant activity against a chloroquine-resistant strain (strain K-1) and a chloroquine-susceptible strain (strain FCR-3) in vitro. The 50% inhibitory concentrations of HT-AMB were 0.32 ؎ 0.03 g/ml for strain K-1 and 0.33 ؎ 0.03 g/ml for strain FCR-3. In the presence of 1.0 g of HT-AMB per ml, only pyknotic parasites were observed after 24 h of incubation of early trophozoites (ring forms). However, when late trophozoites and schizonts were cultured with 1.0 g of HT-AMB per ml, those forms multiplied to ring forms but the number of infected erythrocytes did not increase. These results indicate that HT-AMB possesses potent antiplasmodial activity and that the drug is more effective against the ring-form stage than against the late trophozoite and schizont stages. HT-AMB was observed to have little cytotoxic effect against a human liver cell line (Chang liver cells). In conclusion, the results suggest that HT-AMB has promising properties and merits further in vivo investigations as a treatment for falciparum malaria.Malaria infection due to Plasmodium falciparum is a major public health problem in many tropical and subtropical areas. Sporozoites, the infective form of the parasite, are transferred to the human host during a bite by female Anopheles mosquitoes, invade hepatocytes, and develop into liver schizonts, which contain large numbers of merozoites. The asexual bloodstage cycle of P. falciparum commences when the merozoites released from hepatocytes enter the blood circulation and invade red blood cells (RBCs). In this phase of the cycle merozoites initially develop within RBCs as ring forms and then progress to trophozoites and eventually to schizonts, which rupture and release a new wave of merozoites that invade a new batch of RBCs. Chloroquine (CQ), a blood-stage schizonticidal drug, has been the drug of choice for the treatment of falciparum malaria for several decades, but its clinical utility has been greatly reduced in most areas where CQ-resistant malaria is endemic (1, 22). However, CQ remains the most widely used first-line antimalarial drug because it is well tolerated, safe for pregnant women and young children, efficacious against susceptible strains of P. falciparum and the other three human malaria species, and inexpensive. At present, the development of new antimalarial drugs and the use of preexisting drugs in combination are the most important approaches to overcoming the problem of drug resistance.Amphotericin B (AMB) is a heptaene macrolide antibiotic that is active against fungi and yeasts. Fungizone, the commercially available deoxycholate salt for...

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Section: Discussionmentioning

confidence: 99%

Potent Plasmodicidal Activity of a Heat-Induced Reformulation of Deoxycholate-Amphotericin B (Fungizone) against Plasmodium falciparum

Hatabu

Takada

Taguchi

et al. 2005

Antimicrob Agents Chemother

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“…In fact, the difficulties that were initially found to complicate detection of ion channel activity in planar lipid bilayers treated at only one side with AmB (or nystatin) were resolved with the use of thinner model membranes that employed no hydrocarbon solvent or lipids with shorter carbon chain lengths (6)(7)(8). However, in contrast to the results seen with biological membranes, the presence of sterols in planar lipid bilayers is not an absolute requirement for the formation of ion channels by AmB (13). In this respect, it was shown by using an osmotic method that AmB forms two types of ion channels in liposomes and membrane vesicles prepared from sensitive pathogens (14,15).…”

Section: The Formation Of Ion Channels By Amb and Nystatinmentioning

confidence: 99%

The Role of Signaling via Aqueous Pore Formation in Resistance Responses to Amphotericin B

Cohen

2016

Antimicrob Agents Chemother

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Drug resistance studies have played an important role in the validation of antibiotic targets. In the case of the polyene antibiotic amphotericin B (AmB), such studies have demonstrated the essential role that depletion of ergosterol plays in the development of AmB-resistant (AmB-R) organisms. However, AmB-R strains also occur in fungi and parasitic protozoa that maintain a normal level of ergosterol at the plasma membrane. Here, I review evidence that shows not only that there is increased protection against the deleterious consequences of AmB-induced ion leakage across the membrane in these resistant pathogens but also that a set of events are activated that block the cell signaling responses that trigger the oxidative damage produced by the antibiotic. Such signaling events appear to be the consequence of a membrane-thinning effect that is exerted upon lipid-anchored Ras proteins by the aqueous pores formed by AmB. A similar membrane disturbance effect may also explain the activity of AmB on mammalian cells containing Toll-like receptors. These resistance mechanisms expand our current understanding of the role that the formation of AmB aqueous pores plays in triggering signal transduction responses in both pathogens and host immune cells.

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“…1E) (11)(12)(13)(30)(31)(32)(33)(34)(35)(36)(37)). An often invoked alternative model states that indirect effects on global membrane properties, rather than any direct binding interactions, are responsible for the impacts of membrane sterols on the biological activity of AmB (21)(22)(23)(24)(25)(26)(27)(28)(29).…”

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confidence: 99%

“…The first hypothesis states that indirect differential preorganization of membranes caused by different sterols is responsible (21)(22)(23)(24)(25)(26)(27)(28)(29). This model has been invoked to rationalize observations that, although AmB is typically most potent in membranes that contain sterols, increasing quantities of cholesterol (21,22) or ergosterol (23) can actually decrease the capacity for AmB to promote membrane permeabilization.…”

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confidence: 99%

Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities

Palacios

Dailey

Siebert

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

118

134

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Amphotericin B is the archetype for small molecules that form transmembrane ion channels. However, despite extensive study for more than five decades, even the most basic features of this channel structure and its contributions to the antifungal activities of this natural product have remained unclear. We herein report that a powerful series of functional group-deficient probes have revealed many key underpinnings of the ion channel and antifungal activities of amphotericin B. Specifically, in stark contrast to two leading models, polar interactions between mycosamine and carboxylic acid appendages on neighboring amphotericin B molecules are not required for ion channel formation, nor are these functional groups required for binding to phospholipid bilayers. Alternatively, consistent with a previously unconfirmed third hypothesis, the mycosamine sugar is strictly required for promoting a direct binding interaction between amphotericin B and ergosterol. The same is true for cholesterol. Synthetically deleting this appendage also completely abolishes ion channel and antifungal activities. All of these results are consistent with the conclusion that a mycosamine-mediated direct binding interaction between amphotericin B and ergosterol is required for both forming ion channels and killing yeast cells. The enhanced understanding of amphotericin B function derived from these synthesis-enabled studies has helped set the stage for the more effective harnessing of the remarkable ion channel-forming capacity of this prototypical small molecule natural product.

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Amphotericin B Channels in the Bacterial Membrane: Role of Sterol and Temperature

Cited by 64 publications

References 35 publications

Potent Plasmodicidal Activity of a Heat-Induced Reformulation of Deoxycholate-Amphotericin B (Fungizone) against Plasmodium falciparum

Potent Plasmodicidal Activity of a Heat-Induced Reformulation of Deoxycholate-Amphotericin B (Fungizone) against Plasmodium falciparum

The Role of Signaling via Aqueous Pore Formation in Resistance Responses to Amphotericin B

Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities

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