ABSTRACT
Introduction .......................................................................................................... 72 Aminoglycoside Antibiotics ..................................................................... 72 Mode of Action of Aminoglycoside Antibiotics: Interaction with the
Bacterial Ribosome ........................................................................ 73 Aminoglycoside Uptake ........................................................................... 76 Mechanism of Bactericidal Action of Aminoglycosides .......................... 76
Aminoglycoside Resistance ................................................................................. 77 Altered Uptake .......................................................................................... 77 Aminoglycoside Effl ux ............................................................................. 77 Target Modifi cation .................................................................................. 78 Modifi cation of Aminoglycosides ............................................................ 78
O-Phosphotransferases .................................................................. 80 N-Acetyltransferases ...................................................................... 82 O-Nucleotidyltransferases .............................................................. 85
Strategies to Circumvent Aminoglycoside-Modifying Enzymes ........................ 87 Summary and Conclusions .................................................................................. 91 Acknowledgments ................................................................................................ 92 References ............................................................................................................ 92
Aminoglycoside antibiotics are positively charged carbohydrate-containing molecules that fi nd clinical use for the treatment of infections caused by both Gram-negative and Gram-positive bacteria. The fi rst aminoglycosides were discovered over 60 years ago and several continue to fi nd important clinical use including gentamicin, tobramycin, amikacin, netilmicin, and streptomycin. These antibiotics target the bacterial ribosome and interfere with protein translation. Unlike other antibiotics that block translation, most aminoglycosides are bactericidal, a highly desirable feature in an antiinfective chemotherapeutic agent. The bactericidal action of aminoglycosides is correlated with the propensity to cause misreading of the mRNA transcript resulting in the production of aberrant proteins.
