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

• Published in: Journal of the American Chemical Society Vol. 128; no. 1; pp. 100 - 116
• Main Authors: Bastida, Agatha, Hidalgo, Ana, Chiara, Jose Luis, Torrado, Mario, Corzana, Francisco, Pérez-Cañadillas, Jose Manuel, Groves, Patrick, Garcia-Junceda, Eduardo, Gonzalez, Carlos, Jimenez-Barbero, Jesús, Asensio, Juan Luis
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.01.2006; Amer Chemical Soc
• Subjects: Acetyltransferases - chemistry; Acetyltransferases - metabolism; Aminoglycosides - chemical synthesis; Aminoglycosides - chemistry; Aminoglycosides - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Biological and medical sciences; Carbohydrate Conformation; Carbohydrates with 4, 5, 6, ... C atoms, dissacharides and oligosaccharides; Carbohydrates. Nucleosides and nucleotides; Chemistry; Chemistry, Multidisciplinary; Drug Resistance, Bacterial; Escherichia coli - drug effects; Exact sciences and technology; Framycetin - analogs & derivatives; Framycetin - chemical synthesis; General pharmacology; Medical sciences; Microbial Sensitivity Tests; Models, Molecular; Nuclear Magnetic Resonance, Biomolecular; Nucleotidyltransferases - chemistry; Nucleotidyltransferases - metabolism; Organic chemistry; Pharmacology. Drug treatments; Phosphotransferases (Alcohol Group Acceptor) - chemistry; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Physical Sciences; Physicochemical properties. Structure-activity relationships; Preparations and properties; Ribose - chemistry; RNA - chemistry; RNA - metabolism; Science & Technology; Structure-Activity Relationship; SITE; ANTIBIOTICS; COMPLEX; MOLECULAR RECOGNITION; CRYSTAL-STRUCTURE; DYNAMICS; NMR STRUCTURE; NEOMYCIN; RIBOSOMAL-RNA; BINDING; Organic synthesis; Antibiotic; Structure activity relation; Molecular structure; Aminoglycoside; Overhauser effect; Homonuclear correlation; NMR spectrometry; Antibacterial agent; Conformational changes; Biological activity; Two dimension spectrometry
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja0543144

The 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.