Aminoglycoside Resistance Mechanisms

The major target of aminoglycosides is the bacterial ribosome, as first suggested by in vivo experiments demonstrating a marked decrease in protein synthesis following treatment of cells with aminoglycosides and in vitro experiments on bacterial extracts showing that aminoglycoside treatment resulted in repression of both initiation and elongation in protein synthesis. Chemical footprinting studies and careful correlation analysis of ribosomal mutation with aminoglycoside resistance implicated specific ribosomal proteins and the tRNA binding site (A site) of the 16S rRNA as the most important determinants of aminoglycoside binding and action. There is some evidence that, at least in Escherichia coli, the oligopeptide binding protein, the periplasmic component of the major oligopeptide transport system, may play an important role in aminoglycoside uptake as mutants with reduced oligopeptide binding protein expression are resistant to aminoglycosides. The most common aminoglycoside kinases are APH(3')‐IIIa and APH(2”)‐Ia [C‐terminal domain of the bifunctional aminoglycoside phosphotransferase‐acetyltransferase AAC(6')‐APH(2”)] in gram‐positive organisms, and APH(3')‐Ia and APH(3')‐IIa in gramnegative organisms. APH(3')‐I is the most common class of aminoglycoside kinase in gram‐negative bacteria. ANT(2”)‐Ia is one of the most important determinants of aminoglycoside resistance in gram‐negative organisms. However, molecular research over the last decade has resulted in an excellent understanding of the mode of action, interaction with target, and various resistance mechanisms.