Biochem Pharmacol 1985 Apr 1;34(7):1035-47

Interaction of streptomycin and streptomycylamine derivatives with negatively
charged lipid layers. Correlation between binding, conformation of complexes and
inhibition of lysosomal phospholipase activities.

Brasseur R, Carlier MB, Laurent G, Claes PJ, Vanderhaeghe HJ, Tulkens PM,
Ruysschaert JM

Aminoglycoside antibiotics induce a lysosomal phospholipidosis in kidney
proximal tubules after conventional therapy in animals and man. We have
previously demonstrated that these drugs bind to negatively charged phospholipid
bilayers at acid pH and inhibit the activity of lysosomal acid phospholipases in
vitro and in vivo. A combined biochemical and conformational study [Brasseur et
al., Biochem. Pharmac. 33, 629 (1984)] showed major and consistent differences
between 6 aminoglycosides in current clinical use with respect to the stability
of the complexes they form with phosphatidylinositol, their inhibitory potency
towards the activity of lysosomal phospholipases and their current toxicity
ranking (e.g. gentamicin greater than amikacin greater than streptomycin). In
the present study we have extended this approach to experimental derivatives of
streptomycin. The derivatives examined were: dihydrostreptomycin,
dideguanyldihydrostreptomycin, streptomycylamine, dideguanylstreptomycylamine,
N-butyl- and N-benzyl-dideguanylstreptomycylamine. These compounds were examined
for (i) their binding to negatively charged liposomes, measured by gel
permeation on Sepharose 4B; (ii) their interactions with phosphatidylinositol
assessed by semi-empirical conformational analysis and (iii) their inhibitory
effect on the activities of lysosomal phospholipases towards phosphatidylcholine
present in negatively charged liposomes. Streptomycin and gentamicin were also
used as reference compounds with low and high affinity (and inhibitory potency),
respectively. Our observations can be summarized as follows: (i) the replacement
of the aldehyde in the streptose ring by a methylamino group strikingly changes
the conformation of the molecule, allowing a better interaction with
phosphatidylinositol. Thus, streptomycylamine binds much more tightly to
phospholipid bilayers and shows a higher inhibitory potency towards
phospholipase activity, as compared to streptomycin. The conformational analysis
shows, however, that this effect is only partially due to the additional
cationic charge carried by streptomycylamine. Other modifications of the
streptomycin molecule, such as the replacement of the guanidinium groups by
aminogroups or the addition of hydrophobic moieties (butyl or benzyl groups) to
the streptose do not markedly further strengthen the interactions of the
molecule with phosphatidylinositol. (ii) Even though some derivatives (e.g.
dideguanylstreptomycylamine) bind as tightly to phospholipids as gentamicin,
they remain much less inhibitory towards lysosomal phospholipases.(ABSTRACT
TRUNCATED AT 400 WORDS)

PMID: 3985990, UI: 85174515