An Advanced Apralog with Increased in-vitro and in-vivo Activity toward Gram-negative Pathogens and Reduced ex-vivo Cochleotoxicity.
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-ribosfuranosyl 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 cell-free translation assay, while retaining the excellent cross-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.
PMID: 33007139 [PubMed - as supplied by publisher]
Source: ChemMedChem - Category: Chemistry Authors: Crich D, Sonousi A, Quirke J, Waduge P, Janusic T, Gysin M, Haldimann K, Hobbie S, Sha SH, Schacht J, Christine C, Andrea V, Bottger EC, Xu S Tags: ChemMedChem Source Type: research