Taming Amphotericin B

Janout, Václav; Schell, Wiley A.; Thévenin, Damien; Yu, Yuming; Perfect, John R.; Regen, Steven L.

doi:10.1021/acs.bioconjchem.5b00463

Cited by 33 publications

(55 citation statements)

References 27 publications

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“…94) to alternative structures, such as nanoparticles 95 and conjugated polysaccharides 96,97 , that may be able to penetrate certain body compartments and reduce membrane toxicity 97,98 . One proposed mechanism for this reduced toxicity is that the aggregated forms of amphotericin B have very different activities (specifically toxicities) compared with monomers: aggregates target host cells and thereby increase toxicity, whereas the monomers should target fungi preferentially over the host cells 99 . Another considerable advance in this area has been to produce an oral formulation for polyene treatment.…”

Section: Improving Existing Antifungalsmentioning

confidence: 99%

The antifungal pipeline: a reality check

Perfect

2017

Nat Rev Drug Discov

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634

575

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Invasive fungal infections continue to appear in record numbers as the immunocompromised population of the world increases, owing partially to the increased number of individuals who are infected with HIV and partially to the successful treatment of serious underlying diseases. The effectiveness of current antifungal therapies — polyenes, flucytosine, azoles and echinocandins (as monotherapies or in combinations for prophylaxis, or as empiric, pre-emptive or specific therapies) — in the management of these infections has plateaued. Although these drugs are clinically useful, they have several limitations, such as off-target toxicity, and drug-resistant fungi are now emerging. New antifungals are therefore needed. In this Review, I discuss the robust and dynamic antifungal pipeline, including results from preclinical academic efforts through to pharmaceutical industry products, and describe the targets, strategies, compounds and potential outcomes.

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Section: Improving Existing Antifungalsmentioning

confidence: 99%

The antifungal pipeline: a reality check

Perfect

2017

Nat Rev Drug Discov

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634

575

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“…The success of this strategy is also a consequence of the targeted enhancement of monomeric AmB inside cells by the internalization of the drugloaded lipid particles. Development of new protected monomeric AmB conjugates unable to insert into the membrane but capable of cellular internalization may also kill pathogens by extracting ergosterol from membranes (97).…”

Section: Conclusion and Perpectivesmentioning

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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“…12,15 We refer to the latter as “taming”. 15 Here, we report a minimalistic approach for taming a membrane-disrupting antibiotic that is much simpler than a design principle and modifying agents (i.e., molecular umbrellas) previously used. 15 …”

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confidence: 99%

Simple Strategy for Taming Membrane-Disrupting Antibiotics

Sabulski

Schell

et al. 2016

Bioconjugate Chem.

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A strategy has been devised for increasing the cellular selectivity of membrane-disrupting antibiotics based on the attachment of a facially amphiphilic sterol. Using Amphotericin B (AmB) as a prototype, covalent attachment of cholic acid bound to a series of α,ω-diamines has led to a dramatic reduction in hemolytic activity, a significant reduction in toxicity toward HEK293T cells, and significant retention of antifungal activity.

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Taming Amphotericin B

Cited by 33 publications

References 27 publications

The antifungal pipeline: a reality check

The antifungal pipeline: a reality check

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

Simple Strategy for Taming Membrane-Disrupting Antibiotics

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