An Advanced Apralog with Increased in- vitro and in- vivo Activity toward Gram- negative Pathogens and Reduced ex vivo Cochleotoxicity

Abstract

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 (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.A next- generation aminoglycoside antibiotic based on the apralog concept is presented that displays excellent activity in- vivo and in- vitro, excellent across- the- board selectivity for the inhibition of bacterial over hybrid eukaryotic ribosomes, minimal ototoxicity in an ex vivo model, and which circumvents AAC(3)- IV, the only current aminoglycoside- modifying enzyme acting on the parent.