New derivatives of kanamycin B obtained by combined modifications in positions 1 and 6". Synthesis, microbiological properties, and in vitro and computer-aided toxicological evaluation.

Substitution of the C-1 atom in the 2-deoxystreptamine moiety of gentamicin C2, a broad-spectrum aminoglycoside antibiotic, by an axial hydroxymethyl group has been reported to confer protection against most clinically important bacterial enzymes inactivating aminoglycosides, while simultaneously reducing the nephrotoxic potential of this drug. We report here on a similar modification of kanamycin B. Microbiological evaluation, however, revealed no useful protection, as established by the almost complete lack of activity of 1-C-(hydroxymethyl)kanamycin B against an array of organisms producing defined types of aminoglycoside-inactivating enzymes and against which 1-C-(hydroxymethyl)gentamicin C2 and amikacin (1-N-[(S)-2-hydroxy-4-aminobutyryl]kanamycin A) are active.

New derivatives of kanamycin B obtained by modifications and substitutions in position 6''. 2. In vitro and computer-aided toxicological evaluation with respect to interactions with phosphatidylinositol.

In a companion paper (previous paper in this issue), we report on the synthesis and microbiological evaluation of new derivatives of the aminoglycoside antibiotic kanamycin B carrying substitutions in 6" (halogeno, or amino, amido, thioalkyl, and alkoxy groups, each series with increasingly bulkier chains). These modifications were intended to potentially modulate the interactions of kanamycin B with phospholipids since these are related to inhibition of lysosomal phospholipase activities and lysosomal phospholipidosis, an early and predictive index of the nephrotoxic potential of aminoglycosides. The new derivatives were therefore examined for inhibitory potency in vitro toward lysosomal phospholipase A1 acting on phosphatidylcholine included in negatively charged liposomes.

New derivatives of kanamycin B obtained by modifications and substitutions in position 6". 1. Synthesis and microbiological evaluation.

The clinical use of the potent, wide-spectrum aminoglycoside antibiotics is limited by oto- and nephrotoxicities. The latter is related to the binding of these polycationic drugs to negatively charged phospholipids and to the subsequent inhibition of lysosomal phospholipases. In order to explore the influence of a modification of the hydrophobic/hydrophilic balance at a specific site of an aminoglycoside, kanamycin B has been chemically modified in position 6" by substitution of the hydroxyl group with a halogen atom (or a pseudohalogen group), or an amino, an amido, a thioalkyl, or an alkoxy group, each series containing increasingly bulkier chains.

[Nontraditional beta-lactam antibiotics].

In recent years several beta-lactam derivatives have been obtained, which differ markedly from the traditional penicillins and cephalosporins, some of which have been introduced in the clinic. Clavulanic acid has an oxygen atom instead of sulfur but differs also markedly on C2 and C6. This inhibitor of penicillinase is used in association with amoxicillin and ticarcillin.

Tissue distribution and excretion of radioactively labelled compounds in the Wistar rat after administration of [N-methyl-14C]-erythromycin A.

Tissue distribution and excretion of radioactively labelled compounds was studied in the Wistar rat after i.v. administration of [N-methyl-14C]-erythromycin A.