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An Advanced Apralog with Increased in vitro and in vivo Activity toward Gram‐negative Pathogens and Reduced ex vivo Cochleotoxicity
Author(s) -
Sonousi Amr,
Quirke Jonathan C. K.,
Waduge Prabuddha,
Janusic Tanja,
Gysin Marina,
Haldimann Klara,
Xu Shan,
Hobbie Sven N.,
Sha SuHua,
Schacht Jochen,
Chow Christine S.,
Vasella Andrea,
Böttger Erik C.,
Crich David
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000726
Subject(s) - in vivo , aminoglycoside , ex vivo , antibacterial activity , ribosome , chemistry , in vitro , microbiology and biotechnology , biology , biochemistry , bacteria , antibiotics , rna , gene , genetics
We describe the convergent synthesis of a 5‐ O ‐β‐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 ‐β‐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 (IC 50 ) 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.