The use of aminoglycoside derivatives to study the mechanism of aminoglycoside 6'-N-acetyltransferase and the role of 6'-NH2 in antibacterial activity.
Aminoglycoside antibiotics act by binding to 16S rRNA. Resistance to these antibiotics occurs via drug modifications by enzymes such as aminoglycoside 6'-N-acetyltransferases (AAC(6')s). We report here the regioselective and efficient synthesis of N-6'-acylated aminoglycosides and their use as probes to study AAC(6')-Ii and aminoglycoside-RNA complexes. Our results emphasize the central role of N-6' nucleophilicity for transformation by AAC(6')-Ii and the importance of hydrogen bonding between 6'-NH(2) and 16S rRNA for antibacterial activity.
Yan
Xuxu
X
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, Que., Canada H3A 2K6.
Gao
Feng
F
Yotphan
Sirilata
S
Bakirtzian
Parseh
P
Auclair
Karine
K
D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D000617:Aminoglycosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D002855:Chromatography, Thin Layer; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D012336:RNA, Ribosomal, 16S / Q000378:metabolism; D013329:Structure-Activity Relationship
D000588:Amines; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D007202:Indicators and Reagents; D012336:RNA, Ribosomal, 16S; D000123:Acetyltransferases; C056532:aminoglycoside N(6')-acetyltransferase