Modification at the 2′-Position of the 4,5-Series of 2-Deoxystreptamine Aminoglycoside Antibiotics To Resist Aminoglycoside Modifying Enzymes and Increase Ribosomal Target Selectivity
| Autor: | Erik C. Böttger, David Crich, Sven N. Hobbie, Sujit Mondal, Takayuki Furukawa, Andrea Vasella, Vikram A. Sarpe, Matilde Mantovani, Girish C. Sati |
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| Přispěvatelé: | University of Zurich, Crich, David |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
synthesis Paromomycin 030106 microbiology 610 Medicine & health Microbial Sensitivity Tests decoding A site Ribosome Ribostamycin 03 medical and health sciences Structure-Activity Relationship Drug Resistance Multiple Bacterial multidrug-resistant infectious diseases medicine Protein biosynthesis Humans aminoglycosides selectivity Binding Sites Bacteria 10179 Institute of Medical Microbiology Chemistry Aminoglycoside Hexosamines Neomycin 2725 Infectious Diseases Ribosomal RNA 3. Good health Anti-Bacterial Agents 030104 developmental biology Infectious Diseases Aminoglycosides Biochemistry Protein Biosynthesis 570 Life sciences biology Antibacterial activity Ribosomes medicine.drug |
| Zdroj: | ACS Infectious Diseases, 5 (10) |
| ISSN: | 2373-8227 |
| Popis: | A series of derivatives of the 4,5-disubstituted class of 2-deoxystreptamine aminoglycoside antibiotics neomycin, paromomycin, and ribostamycin was prepared and assayed for (i) their ability to inhibit protein synthesis by bacterial ribosomes and by engineered bacterial ribosomes carrying eukaryotic decoding A sites, (ii) antibacterial activity against wild type Gram negative and positive pathogens, and (iii) overcoming resistance due to the presence of aminoacyl transferases acting at the 2′-position. The presence of five suitably positioned residual basic amino groups was found to be necessary for activity to be retained upon removal or alkylation of the 2′-position amine. As alkylation of the 2′-amino group overcomes the action of resistance determinants acting at that position and in addition results in increased selectivity for the prokaryotic over eukaryotic ribosomes, it constitutes an attractive modification for introduction into next generation aminoglycosides. In the neomycin series, the installation of small (formamide) or basic (glycinamide) amido groups on the 2′-amino group is tolerated. ACS Infectious Diseases, 5 (10) ISSN:2373-8227 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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