[en] Aminoglycoside antibiotics induce an early and characteristic lysosomal phospholipidosis in cultured fibroblasts and in kidney tubular cells. We have recently demonstrated an inhibition of lysosomal phospholipases A1 and A2 by gentamicin and amikacin in vitro. In vivo, gentamicin decreases the activity of phospholipase A1 (Laurent et al., Biochem. Pharmacol. 31:3861-3870, 1982). In the present study, we examined 14 aminoglycosides for in vitro inhibition of phospholipases. To mimic the situation prevailing in lysosomes, the enzymatic activities were assayed with phospholipid vesicles (liposomes) with a composition similar to that of lysosomal phospholipids (phosphatidylcholine, sphingomyelin, phosphatidylinositol, cholesterol; 4:4:3:5.5, molar ratio). We measured the hydrolysis of 1-palmitoyl-2-[1-14C]oleoyl phosphatidylcholine contained in the liposomes by a soluble fraction of highly purified lysosomes isolated from rat liver. Similar IC50S (concentrations causing 50% inhibition of enzymatic activity) were observed for dibekacin, gentamicin (with no major difference between C1, C1a, or C2), netilmicin, tobramycin, and kanamycin B. Sisomicin was slightly more inhibitory. Kanamycin A, N1-(L-4-amino-2-hydroxy-1-oxobutyl)dibekacin, and amikacin showed increasing IC50S. Streptomycin caused the least inhibition. Octa- and tetramethylkanamycin A are much less inhibitory than the parent drug. These results point to the number, the nature, and the respective positions of the cationic groups as essential determinants in causing inhibition of phospholipid breakdown. The binding of three aminoglycosides (gentamicin, amikacin, streptomycin) to the liposomes at pH 5.4 was also measured by gel permeation and was found to be related to the respective inhibitory potency of each drug. Insofar as lysosomal phospholipidosis is an early sign of intoxication by aminoglycosides, these results may serve as a basis for the development or screening of less toxic compounds in this class of antimicrobial agents
