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.
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.
Montenez
J P
JP
Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, Brussels, B-1200, Belgium.
Van Bambeke
F
F
Piret
J
J
Brasseur
R
R
Tulkens
P M
PM
Mingeot-Leclercq
M P
MP
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D017963:Azithromycin / Q000737:chemistry / Q000494:pharmacology; D002474:Cell-Free System; D002478:Cells, Cultured; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004917:Erythromycin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D018942:Macrolides; D008968:Molecular Conformation; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism; D054466:Phospholipases A1; D010743:Phospholipids / Q000737:chemistry* / Q000494:pharmacology; D015575:Roxithromycin / Q000737:chemistry / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D018942:Macrolides; D010743:Phospholipids; C053853:dirithromycin; D015575:Roxithromycin; D004917:Erythromycin; D017963:Azithromycin; D010741:Phospholipases A; D054466:Phospholipases A1