ALTERATIONS IN MEMBRANE-PERMEABILITY INDUCED BY AMINOGLYCOSIDE ANTIBIOTICS - STUDIES ON LIPOSOMES AND CULTURED-CELLS

Aminoglycoside antibiotics bind to negatively-charged membranes in vit ro as well as in vivo. We have examined if this binding could be assoc iated with a change in the properties of membrane permeability. We hav e used a series of aminoglycoside derivatives and two independent test systems, namely (i) the release of calcein and of Mn2+ from phosphati dylinositol-containing large unilamellar vesicles, and (ii) the influx of Ca2+ into cultured macrophages. We found that certain aminoglycosi des (e.g., streptomycin, isepamicin) markedly increase the membrane pe rmeability whereas others (e.g., gentamicin) barely or do not influenc e it. This increase, when it occurs, is slower or less extensive than observed with pore-forming agents (mellitin, nystatin) or a Ca2+-ionop hore (ionomycin). It is not observed with an agent [bis(beta-diethylam inoethylether)hexestrol] known to cause membrane fusion, and is not as sociated with any detectable change in membrane fluidity. In computer- aided conformational analysis of mixed monolayers between phosphatidyl inositol and the aminoglycosides studied, it was found that those deri vatives inducing an increase in membrane permeability in our experimen ts adopted an orientation rather perpendicular to the interface, where as those with no or only a moderate effect were placed in a parallel o rientation to this interface. The perpendicular orientation might caus e a local condition of disorder which could explain the effects observ ed.