A simple structural-based approach to prevent aminoglycoside inactivation by bacterial defense proteins. Conformational restriction provides effective protection against neomycin-B nucleotidylation by ANT4.
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.
Asensio
Juan Luis
JL
Instituto de Química Orgánica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain. iqoa110@iqog.csic.es
Hidalgo
Ana
A
Bastida
Agatha
A
Torrado
Mario
M
Corzana
Francisco
F
Chiara
Jose Luis
JL
García-Junceda
Eduardo
E
Cañada
Javier
J
Jiménez-Barbero
Jesús
J
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
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D005601:Framycetin; D000226:Mitochondrial ADP, ATP Translocases; D009713:Nucleotidyltransferases