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Chapter 7 : Aminoglycoside Resistance Mechanisms

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Abstract:

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 , 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.

Citation: Boehr D, Moore I, Wright G. 2005. Aminoglycoside Resistance Mechanisms, p 85-100. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch7

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Figure 1

Sixty years of aminoglycoside discovery.

Citation: Boehr D, Moore I, Wright G. 2005. Aminoglycoside Resistance Mechanisms, p 85-100. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch7
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Figure 2

Structure and function of aminoglycoside phosphotransferases. (A) Sites of APH-catalyzed phosphorylation of 2-deoxystreptoamine aminoglycosides. (B) Structure of APH(3′)-IIIa, demonstrating the structural similarity eukaryotic Ser/Thr protein kinase A. Inset, blow up of active site region showing five conserved amino acids found in both APHs and protein kinases.

Citation: Boehr D, Moore I, Wright G. 2005. Aminoglycoside Resistance Mechanisms, p 85-100. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch7
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Figure 3

Structure and function of aminoglycoside nucleotidyltransferases. (A) Sites of ANT-catalyzed modification of 2- deoxystreptoamine aminoglycosides. (B) Structure of one monomer of ANT(4′) with inset showing active site residues and orientation of kanamycin and ATP, which lie in the active site formed at the dimer interface.

Citation: Boehr D, Moore I, Wright G. 2005. Aminoglycoside Resistance Mechanisms, p 85-100. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch7
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Figure 4

Structure and function of aminoglycoside acetyltransferases. (A) Sites of AAC-catalyzed acetylation of 2-deoxystreptoamine aminoglycosides. (B) Comparison of the 3D-structures of the AAC subclasses.

Citation: Boehr D, Moore I, Wright G. 2005. Aminoglycoside Resistance Mechanisms, p 85-100. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch7
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Figure 5

Semisynthetic aminoglycosides 5-sisomicin and 5--gentamicin retain antibiotic activity even against bacterial strains harboring ANT(2″), AAC(3), and AAC(2′).

Citation: Boehr D, Moore I, Wright G. 2005. Aminoglycoside Resistance Mechanisms, p 85-100. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch7
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Figure 6

Evasion of APH-mediated resistance by 3′-oxo analogue of kanamycin A.

Citation: Boehr D, Moore I, Wright G. 2005. Aminoglycoside Resistance Mechanisms, p 85-100. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch7
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