UC San Diego

Aminoglycoside amines were globally converted to guanidinium groups to produce guanidinoglycosides. Guanidinoglycosides mostly showed comparable A-site affinities to their parent compounds, but their antibacterial activity was completely compromised. Tobramycin and amikacin, two of the most clinically used aminoglycosides, were selectively modified with various hydrogen bonding moieties at their 6'' positions. Almost all of these analogs had greater affinities for the A- site. Tobramycin derivatives showed overall disappointing antibacterial activity, but several amikacin analogs showed potent and broad-spectrum antibacterial activity against resistant bacteria. Aromatic analogs of the lead compound TAN-1057 were synthesized. Some analogs were evaluated in the previously described manner and also in eukaryotic and prokaryotic in vitro translation assays. The analogs showed inconclusive or poor activity in all assays. An alternate synthesis of the surrogate TAN-1057 side chain, [beta]-lysine was also devised. An inability to resolve racemic β-lysine has thus far stymied the utility of this method, however