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Identification and Evaluation of Improved 4′- O -(Alkyl) 4,5-Disubstituted 2-Deoxystreptamines as Next-Generation Aminoglycoside Antibiotics by Stefan Duscha; Heithem Boukari; Dimitri Shcherbakov; Sumantha Salian; Sandrina Silva; Ann Kendall; Takayuki Kato; Rashid Akbergenov; Deborah Perez-Fernandez; Bruno Bernet; Swapna Vaddi; Pia Thommes; Jochen Schacht; David Crich; Andrea Vasella; Erik C. Böttger is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

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## ABSTRACT The emerging epidemic of drug resistance places the development of efficacious and safe antibiotics in the spotlight of current research. Here, we report the design of next-generation aminoglycosides. Discovery efforts were driven by rational synthesis focusing on 4′ alkylations of the aminoglycoside paromomycin, with the goal to alleviate the most severe and disabling side effect of aminoglycosides—irreversible hearing loss. Compounds were evaluated for target activity in __in vitro__ ribosomal translation assays, antibacterial potency against selected pathogens, cytotoxicity against mammalian cells, and __in vivo__ ototoxicity. The results of this study produced potent compounds with excellent selectivity at the ribosomal target, promising antibacterial activity, and little, if any, ototoxicity upon chronic administration. The favorable biocompatibility profile combined with the promising antibacterial activity emphasizes the potential of next-generation aminoglycosides in the treatment of infectious diseases without the risk of ototoxicity.

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Author

Stefan Duscha; Heithem Boukari; Dimitri Shcherbakov; Sumantha Salian; Sandrina Silva; Ann Kendall; Takayuki Kato; Rashid Akbergenov; Deborah Perez-Fernandez; Bruno Bernet; Swapna Vaddi; Pia Thommes; Jochen Schacht; David Crich; Andrea Vasella; Erik C. Böttger

Publisher

American Society for Microbiology

Published

2014

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)