Interactions Of Macrolide Antibiotics (Erythromycin A, Roxithromycin, Erythromycylamine [Dirithromycin], And Azithromycin) With Phospholipids: Computer-Aided Conformational Analysis And Studies On Acellular And Cell Culture Models
[en] The potential of 14/15 membered macrolides to cause phospholipidosis has been
prospectively assessed, and structure-effects examined, using combined
experimental and conformational approaches. Biochemical studies demonstrated drug
binding to phosphatidylinositol-containing liposomes and inhibition of the
activity of lysosomal phospholipase A1 toward phosphatidylcholine included in the
bilayer, in close correlation with the number of cationic groups carried by the
drugs (erythromycin A </= roxithromycin < erythromycylamine </= azithromycin). In
cultured cells (fibroblasts), phospholipidosis (affecting all major phospholipids
except sphingomyelin) was observed after 3 days with the following ranking:
erythromycin A </= roxithromycin < erythromycylamine < azithromycin
(roxithromycin could, however, not be studied in detail due to intrinsic
toxicity). The difference between erythromycylamine and azithromycin was
accounted for by the lower cellular accumulation of erythromycylamine. In
parallel, based on a methodology developed and validated to study drug-membrane
interactions, the conformational analyses revealed that erythromycin A,
roxithromycin, erythromycylamine, and azithromycin penetrate into the hydrophobic
domain of a phosphatidylinositol monolayer through their desosamine and cladinose
moieties, whereas their macrocycle is found close to the interface. This position
allows the aminogroups carried by the macrocycle of the diaminated macrolides
(erythromycylamine and azithromycin) to come into close contact with the
negatively charged phosphogroup of phosphatidylinositol, whereas the amine
located on the C-3 of the desosamine, common to all four drugs, is located at a
greater distance from this phosphogroup. Our study suggests that all macrolides
have the potential to cause phospholipidosis but that this effect is modulated by
toxicodynamic and toxicokinetic parameters related to the drug structure and
mainly to their cationic character.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Montenez, Jp.
Van Bambeke, F.
Piret, J.
Brasseur, Robert ; Université de Liège - ULiège > Gembloux Agro-Bio Tech
Tulkens, Pm.
Mingeot-Leclercq, Marie-Paule
Language :
English
Title :
Interactions Of Macrolide Antibiotics (Erythromycin A, Roxithromycin, Erythromycylamine [Dirithromycin], And Azithromycin) With Phospholipids: Computer-Aided Conformational Analysis And Studies On Acellular And Cell Culture Models
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