ChemMedChem

Cover image for Vol. 9 Issue 9

Editor-in-Chief: Natalia Ortúzar

Impact Factor: 3.046

ISI Journal Citation Reports © Ranking: 2013: 18/58 (Chemistry Medicinal); 74/254 (Pharmacology & Pharmacy)

Online ISSN: 1860-7187

Associated Title(s): Angewandte Chemie International Edition, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemBioChem, Medicinal Research Reviews, Molecular Informatics

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EarlyViewImportance of the 6'-Hydroxy Group and Its Configuration for Apramycin Activity

Appi Reddy Mandhapati, Dimitri Shcherbakov, Stefan Duscha, Andrea Vasella,* Erik C. Böttger,* David Crich*

The search for novel antibacterial drugs is driven by the widespread emergence of drug-resistant infectious diseases. The relative lack of success of combinatorial drug discovery platforms in this area suggests a renewed focus on the optimization of established drug classes such as the aminoglycoside antibiotics. Most aminoglycoside antibiotics in current use suffer from toxicity problems, the most serious of which is drug-induced ototoxicity.

In this tri-institutional collaboration the groups of microbiologist Erik Böttger of the University of Zürich and organic chemists Andrea Vasella and David Crich of the ETH Zürich and Wayne State University, respectively, focus on apramycin, an aminoglycoside antibiotic currently only used in veterinary medicine, that has previously been demonstrated to be substantially ototoxicity-free and efficacious in the treatment of methicillin-resistant Staphylococcus aureus in animal models.

Through a series of chemical modifications, binding measurements with wild-type bacterial and mutant hybrid ribosomes, and antibacterial assays, the authors uncovered the critical importance of the 6'-hydroxy group of apramycin and of its stereochemical configuration, for differential binding to the decoding A site of the target bacterial ribosomes and to the decoding A site of eukaryotic ribosomes – the probable cause of aminoglycoside ototoxicity. These studies lay the foundation for the rational development of future generations of less toxic and apramycin-class aminoglycoside antibiotics for the treatment of drug-resistant infectious diseases.

Received April 25, 2014; published online July 17, 2014, DOI: 10.1002/cmdc.201402146.

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