Identification and Evaluation of Improved 4′-O-(Alkyl) 4,5-Disubstituted 2-Deoxystreptamines as Next-Generation Aminoglycoside Antibiotics

Abstract

The emerging epidemic of drug resistance places the development of efficacious and safe antibiotics in the spotlight ofcurrent research. Here, we report the design of next-generation aminoglycosides. Discovery efforts were driven by rational syn-thesis focusing on 4=alkylations of the aminoglycoside paromomycin, with the goal to alleviate the most severe and disablingside effect of aminoglycosides—irreversible hearing loss. Compounds were evaluated for target activity inin vitroribosomaltranslation assays, antibacterial potency against selected pathogens, cytotoxicity against mammalian cells, andin vivoototoxic-ity. The results of this study produced potent compounds with excellent selectivity at the ribosomal target, promising antibacte-rial activity, and little, if any, ototoxicity upon chronic administration. The favorable biocompatibility profile combined with thepromising antibacterial activity emphasizes the potential of next-generation aminoglycosides in the treatment of infectious dis-eases without the risk of ototoxicity.