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Exploring the Use of Conformationally Locked Aminoglycosides as a New Strategy to Overcome Bacterial Resistance

AuthorsBastida, Agatha; Hidalgo, Ana; Chiara, José Luis ; Torrado, Mario; Corzana, Francisco; Pérez Cañadillas, José Manuel ; Groves, Patrick ; García-Junceda, Eduardo ; González, Carlos ; Jiménez-Barbero, Jesús ; Asensio, Juan Luis
Issue Date2006
PublisherAmerican Chemical Society
CitationJournal of the American Chemical Society 128(1): 100-116 (2006)
AbstractThe emergence of bacterial resistance to the major classes of antibiotics has become a serious problem over recent years. For aminoglycosides, the major biochemical mechanism for bacterial resistance is the enzymatic modification of the drug. Interestingly, in several cases, the oligosaccharide conformation recognized by the ribosomic RNA and the enzymes responsible for the antibiotic inactivation is remarkably different. This observation suggests a possible structure-based chemical strategy to overcome bacterial resistance; in principle, it should be possible to design a conformationally locked oligosaccharide that still retains antibiotic activity but that is not susceptible to enzymatic inactivation. To explore the scope and limitations of this strategy, we have synthesized several aminoglycoside derivatives locked in the ribosome-bound “bioactive” conformation. The effect of the structural preorganization on RNA binding, together with its influence on the aminoglycoside inactivation by several enzymes involved in bacterial resistance, has been studied. Our results indicate that the conformational constraint has a modest effect on their interaction with ribosomal RNA. In contrast, it may display a large impact on their enzymatic inactivation. Thus, the work presented herein provides a key example of how the conformational differences exhibited by these ligands within the binding pockets of the ribosome and of those enzymes involved in bacterial resistance can, in favorable cases, be exploited for designing new antibiotic derivatives with improved activity in resistant strains.
Description17 páginas, 11 figuras, 1 gráfico, 4 esquemas, 2 tablas.-- Supporting Information Available: Synthesis of derivatives 4 and 5. Supplementary Figures S1 to S7 showing NMR spectra of aminoglycosides 2-6 and solvated MD simulations for derivative 3. This material is available free of charge via the Internet at http://pubs.acs.org.
Publisher version (URL)http://dx.doi.org/10.1021/ja0543144
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