Singly Modified Amikacin and Tobramycin Derivatives Show Increased rRNA A‐Site Binding and Higher Potency against Resistant Bacteria

Semi-synthetic derivatives of clinically useful aminoglycosides, tobramycin and amikacin, were prepared by selectively modifying their 6″ position with a variety of hydrogen bond donors and acceptors. Their binding to the rRNA A-site was probed using an in vitro FRET-based assay and their antibacterial activity against several resistant strains (e.g., P. aeruginosa, K. pneumonia, MRSA) was quantified by determining minimum inhibitory concentrations (MICs). The most potent derivatives were evaluated for their eukaryotic cytotoxicity. Most analogs displayed greater affinity for the bacterial A-site compared to the parent compounds. Although most tobramycin analogs exhibited no improvement antibacterial activity, several amikacin analogs showed potent and broad-spectrum antibacterial activity against resistant bacteria. Derivatives tested for eukaryotic cytotoxicity exhibited minimal toxicity, similar to the parent compounds.