Exploring the use of conformationally locked aminoglycosides as a new strategy to overcome bacterial resistance.
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.
Bastida
Agatha
A
Instituto de Química Orgánica General (CSIC), 28006 Madrid, Spain.
Hidalgo
Ana
A
Chiara
Jose Luis
JL
Torrado
Mario
M
Corzana
Francisco
F
Pérez-Cañadillas
Jose Manuel
JM
Groves
Patrick
P
Garcia-Junceda
Eduardo
E
Gonzalez
Carlos
C
Jimenez-Barbero
Jesús
J
Asensio
Juan Luis
JL
D000123:Acetyltransferases / Q000737:chemistry / Q000378:metabolism; D000617:Aminoglycosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D002236:Carbohydrate Conformation; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects; D005601:Framycetin / Q000031:analogs & derivatives / Q000138:chemical synthesis; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009713:Nucleotidyltransferases / Q000737:chemistry / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D012266:Ribose / Q000737:chemistry; D013329:Structure-Activity Relationship
D000617:Aminoglycosides; D001426:Bacterial Proteins; D005601:Framycetin; D012313:RNA; D012266:Ribose; D000123:Acetyltransferases; C443113:aminoglycoside 2'-N-acetyltransferase; D017853:Phosphotransferases (Alcohol Group Acceptor); C022679:streptomycin 3''-kinase; C428104:Ant(4')-Ia protein, Staphylococcus aureus; D009713:Nucleotidyltransferases