AMINOGLYCOSIDE ANTIBIOTICS INDUCE AGGREGATION BUT NOT FUSION OF NEGATIVELY-CHARGED LIPOSOMES

The binding of aminoglycoside antibiotics to acidic phospholipids of m embranes is an essential step in the development of both their renal a nd auditory toxicities, which could be associated with critical modifi cations of the membrane properties. This work examines the capacity of aminoglycosides to induce membrane aggregation and fusion. Three tech niques were used in parallel: (i) measurement of the dequenching rate of a lipid-soluble fluorescent probe (octadecylrhodamine B) incorporat ed at self-quenched concentration in membranes; (ii) measurement of th e increase in the energy transfer between two fluorescent derivatives of phospholipids; and (iii) electron microscopy of negatively-stained replicas. The results were compared with those obtained with spermine (an aggregating polycation) and melittin (a fusogenic peptide). The th ree approaches indicate that aminoglycosides induce liposomes aggregat ion, but not fusion. Aggregation is related to the capacity of each dr ug studied to bind phosphatidylinositol, as evaluated by its energy of interaction with this acidic phospholipid, and to its toxic potential . Membrane aggregation occurring in vivo could therefore contribute to , or be a determinant of this toxicity, which could rationally be scre ened for new derivatives by the methods applied here.