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

doi:10.1002/cmdc.202000726

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Sonousi, A., Quirke, J. C. K., Waduge, P., Janusic, T., Gysin, M., Haldimann, K., Xu, S., Hobbie, S. N., Sha, S.-H., Schacht, J., Chow, C. S., Vasella, A., Böttger, E. C., & Crich, D. (2021). An Advanced Apralog with Increased in vitro and in vivo Activity toward Gram-negative Pathogens and Reduced ex vivo Cochleotoxicity. ChemMedChem, 16(2), 335–339. https://doi.org/10.1002/cmdc.202000726

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 phosphoryl