An Advanced Apralog with Increased in- vitro and in- vivo Activity toward Gram- negative Pathogens and Reduced ex vivo Cochleotoxicity
dc.contributor.author | Sonousi, Amr | |
dc.contributor.author | Quirke, Jonathan C. K. | |
dc.contributor.author | Waduge, Prabuddha | |
dc.contributor.author | Janusic, Tanja | |
dc.contributor.author | Gysin, Marina | |
dc.contributor.author | Haldimann, Klara | |
dc.contributor.author | Xu, Shan | |
dc.contributor.author | Hobbie, Sven N. | |
dc.contributor.author | Sha, Su‐hua | |
dc.contributor.author | Schacht, Jochen | |
dc.contributor.author | Chow, Christine S. | |
dc.contributor.author | Vasella, Andrea | |
dc.contributor.author | Böttger, Erik C. | |
dc.contributor.author | Crich, David | |
dc.date.accessioned | 2021-02-04T21:54:25Z | |
dc.date.available | 2022-02-04 16:54:22 | en |
dc.date.available | 2021-02-04T21:54:25Z | |
dc.date.issued | 2021-01-19 | |
dc.identifier.citation | 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 (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. | |
dc.identifier.issn | 1860-7179 | |
dc.identifier.issn | 1860-7187 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/166273 | |
dc.description.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. | |
dc.publisher | Wiley Periodicals, Inc. | |
dc.publisher | Springer Science+Business Media | |
dc.subject.other | Drug Design | |
dc.subject.other | Biological Activity | |
dc.subject.other | Antibiotics | |
dc.subject.other | Glycosylation | |
dc.title | An Advanced Apralog with Increased in- vitro and in- vivo Activity toward Gram- negative Pathogens and Reduced ex vivo Cochleotoxicity | |
dc.type | Article | |
dc.rights.robots | IndexNoFollow | |
dc.subject.hlbsecondlevel | Natural Resources and Environmen | |
dc.subject.hlbtoplevel | Science | |
dc.description.peerreviewed | Peer Reviewed | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/166273/1/cmdc202000726_am.pdf | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/166273/2/cmdc202000726.pdf | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/166273/3/cmdc202000726-sup-0001-misc_information.pdf | |
dc.identifier.doi | 10.1002/cmdc.202000726 | |
dc.identifier.doi | https://dx.doi.org/10.7302/196 | |
dc.identifier.source | ChemMedChem | |
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