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-beta-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-beta-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 againstE. coliin a mouse thigh infection model and reduced ototoxicity vis a vis the parent in mouse cochlear explants.

Automated summary

The novel apralog demonstrates significantly improved antibacterial activity against wild-type ESKAPE pathogens compared to the parent compound, while also maintaining excellent activity in the presence of a specific aminoglycoside modifying enzyme. Furthermore, it shows reduced ototoxicity and excellent in vivo efficacy against E. coli in a mouse thigh infection model.