A novel mechanism for an old drug: Amphotericin B in the treatment of visceral leishmaniasis

Chattopadhyay, Amitabha; Jafurulla, Md.

doi:10.1016/j.bbrc.2011.11.023

Cited by 106 publications

(65 citation statements)

References 61 publications

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“…S1A to F in the supplemental material). It is generally believed that amphotericin B is a membrane-active drug that forms channel-like structures (pores) spanning the lipid bilayer (4,8,28). Based on our transmission electron microscopy study and the structural similarities of amphotericin B and corifungin, we believe that the mechanism of action of corifungin against N. fowleri is similar to that of amphotericin B.…”

Section: Discussionmentioning

confidence: 54%

Corifungin, a New Drug Lead against Naegleria, Identified from a High-Throughput Screen

Debnath

Tunac²,

Galindo-Gómez

et al. 2012

Antimicrob Agents Chemother

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c Primary amebic meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living ameba Naegleria fowleri. The drug of choice in treating PAM is the antifungal antibiotic amphotericin B, but its use is associated with severe adverse effects. Moreover, few patients treated with amphotericin B have survived PAM. Therefore, fast-acting and efficient drugs are urgently needed for the treatment of PAM. To facilitate drug screening for this pathogen, an automated, high-throughput screening methodology was developed and validated for the closely related species Naegleria gruberi. Five kinase inhibitors and an NFkappaB inhibitor were hits identified in primary screens of three compound libraries. Most importantly for a preclinical drug discovery pipeline, we identified corifungin, a water-soluble polyene macrolide with a higher activity against Naegleria than that of amphotericin B. Transmission electron microscopy of N. fowleri trophozoites incubated with different concentrations of corifungin showed disruption of cytoplasmic and plasma membranes and alterations in mitochondria, followed by complete lysis of amebae. In vivo efficacy of corifungin in a mouse model of PAM was confirmed by an absence of detectable amebae in the brain and 100% survival of mice for 17 days postinfection for a single daily intraperitoneal dose of 9 mg/kg of body weight given for 10 days. The same dose of amphotericin B did not reduce ameba growth, and mouse survival was compromised. Based on these results, the U.S. FDA has approved orphan drug status for corifungin for the treatment of PAM.

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Section: Discussionmentioning

confidence: 54%

Corifungin, a New Drug Lead against Naegleria, Identified from a High-Throughput Screen

Debnath

Tunac²,

Galindo-Gómez

et al. 2012

Antimicrob Agents Chemother

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“…The drug was first isolated in 1955 from the bacterium Streptomyces nodosus (Chattopadhyay and Jafurulla, 2011). The molecular structure contains 37 carbon atoms with a hydrophobic portion and a sequence of seven conjugated double bonds with lipophilic characteristic containing polar substituents, especially hydroxyls ( Figure 1).…”

Section: Literature Reviewmentioning

confidence: 99%

“…Systemic fungal infections lead to high morbidity and mortality, particularly in patients with weakened immune systems, such as HIV patients, transplant recipients and/or those with hematologic disorders, and those treated with corticosteroids and/or chemotherapy (Chattopadhyay and Jafurulla 2011;Finquelievich et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Difficulties in antifungal therapy with amphotericin B and the continuous search for new formulations: A literature review

Voncik¹,

Fermino²,

Cardoso³

et al. 2016

Afr. J. Pharm. Pharmacol.

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Despite advances in the research on new antifungal agents, Amphotericin B (AmB) is still considered as the antifungal of choice for treating most systemic mycoses due to its potency and broad-spectrum action. However, this drug has limited use because of its toxic effects on kidneys, liver and blood. The search for new and safe formulations of AmB is essential because of the emergence of antifungal resistance to other drugs and the increased number of immunosuppressed patients. Nanoparticles are a promising alternative towards achieving lower toxicity and improved pharmacokinetic properties. This study is a literature review of the use of AmB and the toxicity of formulations. Some of the current new formulations show some advantageous characteristics as compared to AmB. However, there is still need for a continued search for an effectively improved formulation.

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“…Al crear depleción e, incluso, secuestro del colesterol, se evita un número mayor de amastigotes intracelulares 62 . Con base en esto y en el conocimiento de la estructura del parásito con alto contenido de ergosterol, se propuso a AmB como segunda línea de manejo y, dentro de éstas, las formas lipídicas, teniendo en cuenta su capacidad para producir menor nefrotoxicidad 63 , y la alta tasa de respuesta que se encuentra alrededor de 97% de los casos, sin haberse reportado resistencia 64 . Dentro de las formas lipídicas se prefiere AmB liposomal, ya que muestra una mayor efectividad, un aumento en su biodisponibilidad y disminución clara de los efectos adversos 65 .…”

Section: Leishmaniasisunclassified

Formas lipídicas de anfotericina

Botero

Puentes-Herrera

Cortés

2014

Rev. chil. infectol.

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A novel mechanism for an old drug: Amphotericin B in the treatment of visceral leishmaniasis

Cited by 106 publications

References 61 publications

Corifungin, a New Drug Lead against Naegleria, Identified from a High-Throughput Screen

Corifungin, a New Drug Lead against Naegleria, Identified from a High-Throughput Screen

Difficulties in antifungal therapy with amphotericin B and the continuous search for new formulations: A literature review

Formas lipídicas de anfotericina

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