Influence of 4鈥?O-Glycoside Constitution and Configuration on Ribosomal Selectivity of Paromomycin

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• 作者：Takahiko Matsushita ; Weiwei Chen ; Reda Juskeviciene ; Youjin Teo ; Dimitri Shcherbakov ; Andrea Vasella ; Erik C. B枚ttger ; David Crich
• 刊名：Journal of the American Chemical Society
• 出版年：2015
• 出版时间：June 24, 2015
• 年：2015
• 卷：137
• 期：24
• 页码：7706-7717
• 全文大小：673K
• ISSN：1520-5126

文摘

A series of 20 4鈥?O-glycosides of the aminoglycoside antibiotic paromomycin were synthesized and evaluated for their ability to inhibit protein synthesis by bacterial, mitochondrial and cytosolic ribosomes. Target selectivity, i.e., inhibition of the bacterial ribosome over eukaryotic mitochondrial and cytosolic ribosomes, which is predictive of antibacterial activity with reduced ototoxicity and systemic toxicity, was greater for the equatorial than for the axial pyranosides, and greater for the d-pentopyranosides than for the l-pentopyranosides and d-hexopyranosides. In particular, 4鈥?O-尾-d-xylopyranosyl paromomycin shows antibacterioribosomal activity comparable to that of paromomycin, but is significantly more selective showing considerably reduced affinity for the cytosolic ribosome and for the A1555G mutant mitochondrial ribosome associated with hypersusceptibility to drug-induced ototoxicity. Compound antibacterioribosomal activity correlates with antibacterial activity, and the ribosomally more active compounds show activity against Escherichia coli, Klebsiella pneumonia, Enterobacter cloacae, Acinetobacter baumannii, and methicillin-resistant Staphylococcus aureus (MRSA). The paromomycin glycosides retain activity against clinical strains of MRSA that are resistant to paromomycin, which is demonstrated to be a consequence of 4鈥?O-glycosylation blocking the action of 4鈥?aminoglycoside nucleotidyl transferases by the use of recombinant E. coli carrying the specific resistance determinant.