Molecular basis of the nephrotoxicity of aminoglycoside antibiotics: A Fourier transform infrared spectroscopic investigation.

Abstract

The interaction of gentamicin with daptomycin and PI dispersions was investigated by FTIR spectroscopy. We found no evidence of a direct interaction involving the neutralization of the aspartate residues of daptomycin by gentamicin and the amide I band of daptomycin did not reveal significant conformational changes of its peptidic moiety. On the other hand, daptomycin readily inserts within bilayers of PI, dimyristoylphosphatidylglycerol or dipalmitoylphosphatidylcholine, as judged from its influence on the fluidity of these bilayers. The incorporation of daptomycin into PI bilayers has only a slight effect on the lipopeptide amide I band. The affinity of the aminoglycoside for PI is slightly increased in the presence of daptomycin, in agreement with the results of the dialysis study mentioned above. Gentamicin induces a slight narrowing of the amide I band of daptomycin bound to PI bilayers. The fluidity of the lipid bilayers corresponds to that seen in the absence of both drugs. It is proposed that in the presence of the lipopeptide antibiotic, the critical charge density and membrane fluidity required for optimal enzyme activity is restored, explaining its nephroprotective capabilities. The mechanism of nephroprotection by poly-L-aspartic acid is different from that of daptomycin. Dialysis studies have indicated an optimal binding between gentamicin and polyaspartic acid at acidic pH. We found no evidence of a direct interaction involving the neutralization of the carboxylates of polyaspartic acid by gentamicin and the amide I band of polyaspartic acid did not reveal significant conformational changes. On the other hand, polyaspartic acid had no effect on the spectral features of PI bilayers. A reduction in the changes induced by gentamicin in the lipid head group and interfacial region suggests that the affinity of the aminoglycoside antibiotic decreases in the presence of polyaspartic acid. (Abstract shortened by UMI.)