Biochem Pharmacol 1984 Feb 15;33(4):629-37

Interactions of aminoglycoside antibiotics with negatively charged lipid layers.
Biochemical and conformational studies.

Brasseur R, Laurent G, Ruysschaert JM, Tulkens P

Previous studies [Laurent et al., Biochem. Pharmac. 31, 3861 (1982)] have
demonstrated that aminoglycoside antibiotics bind to negatively charged
phospholipid bilayers and inhibit the activity of lysosomal phospholipases. This
inhibition also occurs in vivo in animal and man. It is considered to be an
early and significant step in the development of aminoglycoside-induced
nephrotoxicity. The binding of 6 aminoglycosides in current clinical use
(dibekacin, gentamicin, tobramycin, kanamycin A, amikacin and streptomycin) to
phosphatidylinositol has been studied by gel filtration technique and by
conformational analysis. Variation of the phosphatidylinositol content from 0 to
27% of total phospholipids causes a cooperative increase in aminoglycoside
binding. At fixed phosphatidylinositol concentration, the binding of the
different aminoglycosides is related to the number of aminogroups carried by the
drug (viz., gentamicin greater than kanamycin A greater than streptomycin) and
is largely, but not entirely dependent upon electrostatic interactions.
Conformational analysis of the interaction of aminoglycosides with
phosphatidylinositol monolayers was made by a step-wise computation approach. We
first have taken into account the Vander Waals, torsional and electrostatic
energies and we have calculated the hydrophobic and hydrophilic centers of each
molecule. Assembly was then computed by successive association of one molecule
of drug and up to 4 molecules of phosphatidylinositol. The calculated
interaction energies varied from -8.5 kcal/mol (gentamicin) to -4.9 kcal/mol
(amikacin) and -3.9 kcal/mol (streptomycin).(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 6704179, UI: 84154043