In Vitro Study and Conformational Analysis of 1-N-Aminohydroxybutyryl Derivatives of Aminoglycosides in Correlation with Their Inhibitory Potency Towards Lysosomal Phospholipases

Abstract

Aminoglycoside nephrotoxicity involves the development of a lysosomal phospholipidosis in proximal tubular cells (Tulkens 1986). In vitro, aminoglycosides bind to negatively charged phospholipid bilayers and inhibit the activities of lysosomal phospholipases (Laurent et al. 1982; Mingeot-Leclercq et al. 1987). By computer-aided conformational analysis, it was observed that amikacin, a semisynthetic derivative of kanamycin A in which the N1 aminofunction is substituted by a 4-amino-2-hydroxy-1-oxobutyl (aminohydroxybutyryl, AHBA) moiety and which is reported to be less nephrotoxic than gentamicin and tobramycin (Hottendorf and Gordon 1980; Holm et al. 1983), displays a markedly different mode of insertion and a lower energy of interaction, binds less tightly to negatively charged lipid layers, and is a less potent inhibitor of lysosomal phospholipases than most other 2-deoxystreptamine-containing aminoglycosides (Carlier et al. 1983). This difference, however, could be related to the lower number of cationic charges of amikacin (4) or to the presence of the AHBA side chain. Therefore other experimental aminoglycosides carrying a 1-N-aminohydroxybutyryl side chain and patterned after dibekacin, tobramycin, and kanamycin B, which all possess five amino groups (Fig. 1), have been examined for their ability to bind to negatively charged lipids and inhibit lysosomal phospholipase activity.KeywordsAntimicrob AgentConformational AnalysisInhibitory PotencyProximal Tubular CellAminoglycoside AntibioticThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.