INTERACTION OF THE MACROLIDE AZITHROMYCIN WITH PHOSPHOLIPIDS .1. INHIBITION OF LYSOSOMAL PHOSPHOLIPASE A(1) ACTIVITY

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.