title: 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 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.
  
  
  OBJECTIVE
  The ever-widening epidemic of multidrug-resistant infectious diseases and the paucity of novel antibacterial agents emerging from modern screening platforms mandate the reinvestigation of established drugs with an emphasis on improved biocompatibility and overcoming resistance mechanisms. Here, we describe the preparation and evaluation of derivatives of the established aminoglycoside antibiotic paromomycin that effectively remove its biggest deficiency, ototoxicity, and overcome certain bacterial resistance mechanisms.
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Duscha
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
authors.forename: Heithem
authors.initials: H
authors.lastname: Boukari
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Shcherbakov
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Zürich, Switzerland.
authors.forename: Sumantha
authors.initials: S
authors.lastname: Salian
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Zürich, Switzerland.
authors.forename: Sandrina
authors.initials: S
authors.lastname: Silva
authors.affiliation: Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Kendall
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, Michigan, USA.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kato
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
authors.forename: Rashid
authors.initials: R
authors.lastname: Akbergenov
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Zürich, Switzerland.
authors.forename: Deborah
authors.initials: D
authors.lastname: Perez-Fernandez
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Zürich, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Bernet
authors.affiliation: Euprotec Limited, Manchester, United Kingdom.
authors.forename: Swapna
authors.initials: S
authors.lastname: Vaddi
authors.affiliation: Euprotec Limited, Manchester, United Kingdom.
authors.forename: Pia
authors.initials: P
authors.lastname: Thommes
authors.affiliation: Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jochen
authors.initials: J
authors.lastname: Schacht
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, Michigan, USA.
authors.forename: David
authors.initials: D
authors.lastname: Crich
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Zürich, Switzerland vasella@org.chem.ethz.ch boettger@imm.uzh.ch.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vasella
authors.affiliation: Institut für Medizinische Mikrobiologie, Universität Zürich, Zürich, Switzerland.
authors.forename: Erik C
authors.initials: EC
authors.lastname: Böttger
mesh_terms: D000617:Aminoglycosides / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001424:Bacterial Infections / Q000188:drug therapy; D004926:Escherichia coli / Q000187:drug effects; D006168:Guinea Pigs; D006595:Hexosamines / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D041681:NIH 3T3 Cells; D010802:Phylogeny; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D012270:Ribosomes / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D006595:Hexosamines; D012336:RNA, Ribosomal, 16S; C007265:2-deoxystreptamine