F. Vanbambeke et al., INTERACTION OF THE MACROLIDE AZITHROMYCIN WITH PHOSPHOLIPIDS .1. INHIBITION OF LYSOSOMAL PHOSPHOLIPASE A(1) ACTIVITY, European journal of pharmacology, 314(1-2), 1996, pp. 203-214
Azithromycin, the first clinically developed dicationic macrolide anti
biotic, displays an exceptional accumulation in lysosomes of cultured
cells. In fibroblasts incubated with 50 mg/l (66.6 mu M), it induces a
distinct lysosomal phospholipidosis as evidenced by biochemical and u
ltrastructural criteria, which strikingly resembles alterations descri
bed previously with gentamicin, a pentacationic aminoglycoside antibio
tic which inhibits the lysosomal catabolism of phospholipids. We show
that both drugs inhibit, in an equimolar manner, the activity of phosp
holipase A, (assayed for phosphatidylcholine, included in negatively c
harged liposomes), in a way consistent with the model of 'charge neutr
alization' proposed already for gentamicin (Mingeot-Leclercq et al., 1
988, Biochem. Pharmacol. 37, 591). Both drugs bind to negatively charg
ed liposomes. Yet, in spite of this binding, azithromycin does not ind
uce aggregation or fusion of negatively charged vesicles, under condit
ions in which gentamicin (or spermine, a fully hydrophilic polycation)
causes a massive aggregation, and bis(beta-diethylaminoethylether)hex
estrol (a dicationic amphiphile) causes fusion. The molecular interact
ions of azithromycin with acidic phospholipids are further examined in
a companion paper.