Self-Association of Amphotericin B: Spontaneous Formation of Molecular Structures Responsible for the Toxic Side Effects of the Antibiotic

Amphotericin B (AmB) is a lifesaving antibiotic used to treat deep-seated mycotic infections. Both the pharmaceutical activity and highly toxic side effects of the drug rely on its interaction with biomembranes, which is governed by the molecular organization of AmB. In the present work, we present...

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Bibliographic Details
Published in:The journal of physical chemistry. B 2014-12, Vol.118 (48), p.13821-13832
Main Authors: Starzyk, Joanna, Gruszecki, Marcin, Tutaj, Krzysztof, Luchowski, Rafal, Szlazak, Radoslaw, Wasko, Piotr, Grudzinski, Wojciech, Czub, Jacek, Gruszecki, Wieslaw I
Format: Article
Language:English
Subjects:
Amphotericin B - chemistry
Amphotericin B - metabolism
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - metabolism
Antibiotics
Circular Dichroism
Dimerization
Drugs
Hydrogen Bonding
Hydrogen-Ion Concentration
Kinetics
Liposomes - chemistry
Liposomes - metabolism
Microscopy, Fluorescence
Molecular Dynamics Simulation
Molecular structure
Pharmaceuticals
Self assembly
Side effects
Solvents - chemistry
Static Electricity
Toxic
Toxicology
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Summary:Amphotericin B (AmB) is a lifesaving antibiotic used to treat deep-seated mycotic infections. Both the pharmaceutical activity and highly toxic side effects of the drug rely on its interaction with biomembranes, which is governed by the molecular organization of AmB. In the present work, we present a detailed analysis of self-assembly of AmB molecules in different environments, interesting from the physiological standpoint, based on molecular spectroscopy techniques: electronic absorption, circular dichroism, steady state and time-resolved fluorescence and molecular dynamic calculations. The results show that, in the water medium, AmB self-associates to dimeric structures, referred to as “parallel” and “antiparallel”. AmB dimers can further assemble into tetramers which can play a role of transmembrane ion channels, affecting electrophysiological homeostasis of a living cell. Understanding structural determinants of self-assembly of AmB opens a way to engineering preparations of the drug which retain pharmaceutical effectiveness under reduced toxicity.
ISSN:1520-6106
1520-5207
DOI:10.1021/jp510245n