title: A simple structural-based approach to prevent aminoglycoside inactivation by bacterial defense proteins. Conformational restriction provides effective protection against neomycin-B nucleotidylation by ANT4.
abstract: Herein, we describe how the conformational differences exhibited by aminoglycosides in the binding pockets of the ribosome and those enzymes involved in bacterial resistance can be exploited in the design of new antibiotic derivatives with improved activity in resistant strains. The simple modification shown in the figure, leading to the conformationally restricted 5, provides an effective protection against aminoglycoside inactivation by Staphylococcus aureus ANT4, both in vivo and in vitro.
authors.affiliation: Instituto de Química Orgánica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain. iqoa110@iqog.csic.es
authors.forename: Juan Luis
authors.initials: JL
authors.lastname: Asensio
authors.forename: Ana
authors.initials: A
authors.lastname: Hidalgo
authors.forename: Agatha
authors.initials: A
authors.lastname: Bastida
authors.forename: Mario
authors.initials: M
authors.lastname: Torrado
authors.forename: Francisco
authors.initials: F
authors.lastname: Corzana
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Chiara
authors.forename: Eduardo
authors.initials: E
authors.lastname: García-Junceda
authors.forename: Javier
authors.initials: J
authors.lastname: Cañada
authors.forename: Jesús
authors.initials: J
authors.lastname: Jiménez-Barbero
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002236:Carbohydrate Conformation; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D005601:Framycetin / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D009713:Nucleotidyltransferases / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D005601:Framycetin; D000226:Mitochondrial ADP, ATP Translocases; D009713:Nucleotidyltransferases