Structure and absolute configuration of the polyene macrolide antibiotic amphotericin B

Mechlinski, Witold; Schaffner, Carl P.; Ganis, Paolo; Avitabile, G.

doi:10.1016/s0040-4039(01)98612-5

Cited by 154 publications

(38 citation statements)

References 11 publications

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“…The initial geometries of the studied antibiotics were based on a crystal structure [38]. Additional substituents in PAmE and SAmE were built using InsightII software (Accelrys, San Diego, USA).…”

Section: Pmf Calculationsmentioning

confidence: 99%

Influence of a lipid bilayer on the conformational behavior of amphotericin B derivatives — A molecular dynamics study

Neumann

Borowski

Bagiński

2009

Biophysical Chemistry

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. Influence of a lipid bilayer on the conformational behavior of amphotericin B derivatives -a molecular dynamics study. Biophysical Chemistry, Elsevier, 2009, 141 (1) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Author to whom the correspondence should be addressed. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT3 AbstractAmphotericin B (AmB) is an effective but very toxic antifungal antibiotic. In our laboratory a series of AmB derivatives of improved selectivity of action was synthesized and tested. To understand molecular basis of this improvement, comparative conformational studies of amphotericin B and its two more selective derivatives were carried out in an aqueous solution and in a lipid membrane. These molecular simulation studies revealed that within a membrane environment the conformational behavior of the derivatives differs significantly from the one observed for the parent molecule. Possible reasons for such a difference are analyzed. Furthermore, we hypothesize that the observed conformational transition within the polar head of AmB derivatives may lead to destabilization of antibioticinduced transmembrane channels. Consequently, the selective toxicity of the derivatives should increase as ergosterol-rich liquid-ordered domains are more rigid and conformationally ordered than their cholesterol-containing counterparts, and as such may better support less stable channel structure.

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Section: Pmf Calculationsmentioning

confidence: 99%

Influence of a lipid bilayer on the conformational behavior of amphotericin B derivatives — A molecular dynamics study

Neumann

Borowski

Bagiński

2009

Biophysical Chemistry

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“…It is interesting, however, that filipin (C35H48Q1 1 ; molecular weight 654*9), a relatively small polyene, has been found (see Lampen, 1969) to bring about much more, far-reaching damage to the membranes of susceptible organisms than do either of the larger polyenes, amphotericin B (C47H72Q17N; mol. wt 922.1; Mechlinski et al, 1970) and nystatin (C47H75Q17N; mol. wt 9254 ; Borowski et al, 1971); this may account for the fact that resistance to filipin is less well developed than is resistance to the other two polyenes under consideration.…”

Section: Unabsorbed Absorbedmentioning

confidence: 99%

Physiological Properties Of Mutagen-Induced Variants Of Candida Albicans Resistant To Polyene Antibiotics

Hamilton‐Miller

1972

Journal of Medical Microbiology

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“…benzylamine, and with more complex amines, e.g. the mycosamine-containing antibiotic amphotericin R [14].…”

mentioning

confidence: 99%

Inhibition of the Links between Electron Transfer and Proton Translocation in Mitochondria

Tu¹,

Lam²,

Ramírez³

et al. 1981

European Journal of Biochemistry

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The mechanism by which proton extrusion is linked to electron transfer in mitochondria was investigated by means of the primary amine-specific reagent fluorescamine, and of compounds obtained from the reaction of fluorescamine with simple amines (e.g. benzylamine) and with the mycosamine-containing antibiotic amphotericin B. The effect of these 'modifiers' (i.e. fluorescamine and the acyclic amine-fluorescamine compounds) on the activities of sites I1 and I11 of the electron transfer chain were assayed separately using specific inhibitors to block the action associated with the other site. Both types of modifiers inhibited the proton extrusion across the membrane to a significantly greater extent than the electron transfer process in both sites I1 and 111. I n contrast, the lactone derivative (or cyclic form) of the amine-fluorescamine compounds had no significant inhibitory effect on the proton extrusion and its associated electron transfer. These results are consistent with the hypothesis that the link between proton extrusion and electron transfer in mitochondria is indirect in nature. The results show that: (a) the links involved in sites I1 and I11 are identical or very similar in nature; (b) a covalent modification of primary amino groups in the inner membrane is not essential for the expression of these differential inhibitory effects ; (c) specific structural features in the amine-fluorescamine compounds, and in the mitochondria-fluorescamine derivatives, are crucial for the expression of the inhibitory effects. Our results contradict the 'redox loop' model of Mitchell, and are compatible with the proton pump concept for the linked proton translocation in oxidative phosphorylation.

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Structure and absolute configuration of the polyene macrolide antibiotic amphotericin B

Cited by 154 publications

References 11 publications

Influence of a lipid bilayer on the conformational behavior of amphotericin B derivatives — A molecular dynamics study

Influence of a lipid bilayer on the conformational behavior of amphotericin B derivatives — A molecular dynamics study

Physiological Properties Of Mutagen-Induced Variants Of Candida Albicans Resistant To Polyene Antibiotics

Inhibition of the Links between Electron Transfer and Proton Translocation in Mitochondria

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