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An Advanced Apralog with Increased in vitro and in vivo Activity toward Gram-negative Pathogens and Reduced ex vivo Cochleotoxicity.
Sonousi, Amr; Quirke, Jonathan C K; Waduge, Prabuddha; Janusic, Tanja; Gysin, Marina; Haldimann, Klara; Xu, Shan; Hobbie, Sven N; Sha, Su-Hua; Schacht, Jochen; Chow, Christine S; Vasella, Andrea; Böttger, Erik C; Crich, David.
Afiliación
  • Sonousi A; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
  • Quirke JCK; Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI, 48202, USA.
  • Waduge P; Department of Pharmacy and Biomedical Sciences and Department of Chemistry and Complex Carbohydrate Research Center, University of Georgia, 250 West Green Street, Athens, GA, 30602, USA.
  • Janusic T; Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI, 48202, USA.
  • Gysin M; Institute of Medical Microbiology, University of Zurich, Gloriastrasse 28, 8006, Zürich, Switzerland.
  • Haldimann K; Institute of Medical Microbiology, University of Zurich, Gloriastrasse 28, 8006, Zürich, Switzerland.
  • Xu S; Institute of Medical Microbiology, University of Zurich, Gloriastrasse 28, 8006, Zürich, Switzerland.
  • Hobbie SN; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Walton Research Building, Room 403-E, 39 Sabin Street, Charleston, SC, 29425, USA.
  • Sha SH; Institute of Medical Microbiology, University of Zurich, Gloriastrasse 28, 8006, Zürich, Switzerland.
  • Schacht J; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Walton Research Building, Room 403-E, 39 Sabin Street, Charleston, SC, 29425, USA.
  • Chow CS; Kresge Hearing Research Institute, Department of Otolaryngology, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI, 48109, USA.
  • Vasella A; Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI, 48202, USA.
  • Böttger EC; Organic Chemistry Laboratory, ETH Zürich, Vladimir-Prelog-Weg 1-5/10, 8093, Zürich, Switzerland.
  • Crich D; Institute of Medical Microbiology, University of Zurich, Gloriastrasse 28, 8006, Zürich, Switzerland.
ChemMedChem ; 16(2): 335-339, 2021 01 19.
Article en En | MEDLINE | ID: mdl-33007139
We describe the convergent synthesis of a 5-O-ß-D-ribofuranosyl-based apramycin derivative (apralog) that displays significantly improved antibacterial activity over the parent apramycin against wild-type ESKAPE pathogens. In addition, the new apralog retains excellent antibacterial activity in the presence of the only aminoglycoside modifying enzyme (AAC(3)-IV) acting on the parent, without incurring susceptibility to the APH(3') mechanism that disables other 5-O-ß-D-ribofuranosyl 2-deoxystreptamine type aminoglycosides by phosphorylation at the ribose 5-position. Consistent with this antibacterial activity, the new apralog has excellent 30 nM activity (IC50 ) for the inhibition of protein synthesis by the bacterial ribosome in a cell-free translation assay, while retaining the excellent across-the-board selectivity of the parent for inhibition of bacterial over eukaryotic ribosomes. Overall, these characteristics translate into excellent in vivo efficacy against E. coli in a mouse thigh infection model and reduced ototoxicity vis à vis the parent in mouse cochlear explants.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cóclea / Escherichia coli / Antibacterianos / Nebramicina Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: ChemMedChem Asunto de la revista: FARMACOLOGIA / QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Egipto Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cóclea / Escherichia coli / Antibacterianos / Nebramicina Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: ChemMedChem Asunto de la revista: FARMACOLOGIA / QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Egipto Pais de publicación: Alemania