Modification at the 2'-Position of the 4,5-Series of 2-Deoxystreptamine Aminoglycoside Antibiotics to Resist Aminoglycoside Modifying Enzymes and Increase Ribosomal Target Selectivity.

A series of derivatives of the 4,5-disusbtituted class of 2-deoxystreptamine aminoglycoside antibiotics neomycin, paromomycin, and ribostamycin have been prepared and assayed for i) their ability to inhibit protein synthesis by bacterial ribosomes and by engineered bacterial ribosomes carrying eukaryotic decoding A sites; ii) antibacterial activity against wild type Gram negative and positive pathogens, and iii) overcoming resistance due to the presence of aminoacyl transferases acting at the 2'-position. The presence of five residual basic amino groups was found to be necessary for activity to be retained upon removal or alkylation of the 2'-position amine. As alkylation of the 2'-amino group overcomes the action of resistance determinants acting at that position and in addition results in increased selectivity for the prokaryotic over eukaryotic ribosomes, it constitutes an attractive modification for introduction into next generation aminoglycosides. In the neomycin series the installation of small (formamide) or basic (glycinamide) on the 2'-amino group is tolerated.