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Chapter 34 : Aminoglycoside Antibiotics and Decoding

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Abstract:

Aminoglycoside antibiotics bind directly to 16S rRNA in the 30S subunit of bacterial ribosomes and decrease the fidelity of translation. Aminoglycoside antibiotics remain important therapeutic agents and represent the archetype for RNA-targeted antibiotics. This chapter presents an overview of the investigations of how aminoglycoside antibiotics bind to rRNA and the insights these studies have provided into the decoding process. Throughout the chapter, the term "aminoglycoside" will implicitly refer to this subclass. It is within this conserved decoding region RNA that aminoglycoside antibiotics bind. The chemical groups that are common among aminoglycoside antibiotics direct specific interaction with the RNA. The major sequence difference between all prokaryotic ribosomes and all eukaryotic ribosomes in the aminoglycoside binding site is an A1408-toG1408 change. However, only low-level resistance was observed to G418 and paromomycin, which are the most effective aminoglycosides against eukaryotic organisms. The major mechanism of aminoglycoside resistance is enzymatic modification of the drug. Molecular contacts between A1492 and A1493 and mRNA during decoding may also explain the miscoding induced by aminoglycoside antibiotics. The work on aminoglycoside antibiotics has revealed the details of how aminoglycosides bind to the ribosome, how resistance occurs, and how selectivity for prokaryotes is achieved. Only the combination of structure determination, biochemical, and biophysical approaches provides true insights into the workings of the ribosome. The use of a small oligonucleotide was essential for this work.

Citation: Puglisi J, Blanchard S, Dahlquist K, Eason R, Fourmy D, Lynch S, Recht M, Yoshizawa S. 2000. Aminoglycoside Antibiotics and Decoding, p 419-430. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch34

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Figure 1

Aminoglycoside antibiotics containing a 2-deoxystreptamine ring.

Citation: Puglisi J, Blanchard S, Dahlquist K, Eason R, Fourmy D, Lynch S, Recht M, Yoshizawa S. 2000. Aminoglycoside Antibiotics and Decoding, p 419-430. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch34
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Image of Figure 2
Figure 2

(a) Secondary structure of 16S rRNA, highlighting the decoding region A site. Nucleotides conserved in greater than 95% of ribosomal sequences are shown in outline. Sites of protection from reaction with the chemical probe DMS in the presence of cognate A-site tRNA and mRNA are shown as solid circles. The size of the black dots indicates the relative level of chemical modification in the absence of ligand. Sites of protection from reaction with DMS upon addition of aminoglycoside antibiotics are shown as solid diamonds. (b) Secondary structure of the oligonucleotide construct that mimics the aminoglycoside binding properties of the 30S subunit. Nucleotides that are required for high-affinity binding of aminoglycosides are shown in boldface.

Citation: Puglisi J, Blanchard S, Dahlquist K, Eason R, Fourmy D, Lynch S, Recht M, Yoshizawa S. 2000. Aminoglycoside Antibiotics and Decoding, p 419-430. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch34
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Image of Figure 3
Figure 3

Comparison of the internal loops (A1408, A1492, and A1493) for the free (top) and paromomycin-bound (bottom) forms of the A-site oligonucleotide. The final 20 superimposed NMR structures for each state are shown.

Citation: Puglisi J, Blanchard S, Dahlquist K, Eason R, Fourmy D, Lynch S, Recht M, Yoshizawa S. 2000. Aminoglycoside Antibiotics and Decoding, p 419-430. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch34
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Image of Figure 4
Figure 4

Comparison of the solution structures of the paromomycin- and gentamicin C1a-RNA oligonucleotide complexes. The drugs bind in the major groove of the RNA. Paromomycin is shown in yellow, and gentamicin C1a is in red. The RNA conformations are very similar. RNA in the paromomycin complex is brown, whereas the RNA in the gentamicin C1a complex is tan.

Citation: Puglisi J, Blanchard S, Dahlquist K, Eason R, Fourmy D, Lynch S, Recht M, Yoshizawa S. 2000. Aminoglycoside Antibiotics and Decoding, p 419-430. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch34
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Image of Figure 5
Figure 5

Binding of aminoglycoside antibiotics in the major groove of the A-site RNA oligonucleotide displaces A1492 and A1493 towards the minor groove. The phosphodiester backbone is represented by a yellow ribbon for the free-form RNA and an orange ribbon for the bound-form RNA. The bases A1408, G1491, A1492, and A1493 are shown in olive green for the free form and in lilac for the paromomycin complex.

Citation: Puglisi J, Blanchard S, Dahlquist K, Eason R, Fourmy D, Lynch S, Recht M, Yoshizawa S. 2000. Aminoglycoside Antibiotics and Decoding, p 419-430. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch34
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Figure 6

(A) Schematic showing intermolecular contacts between critical chemical groups in paromomycin and the A-site RNA. (B) Intermolecular contacts observed between gentamicin C1a and the A-site RNA.

Citation: Puglisi J, Blanchard S, Dahlquist K, Eason R, Fourmy D, Lynch S, Recht M, Yoshizawa S. 2000. Aminoglycoside Antibiotics and Decoding, p 419-430. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch34
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Image of Figure 7
Figure 7

Secondary structures of the A-site decoding region in 16S-like rRNAs of three organisms: , and human (cytoplasmic). The G1408 mutation in is indicated. Highly conserved nucleotides are shown in boldface.

Citation: Puglisi J, Blanchard S, Dahlquist K, Eason R, Fourmy D, Lynch S, Recht M, Yoshizawa S. 2000. Aminoglycoside Antibiotics and Decoding, p 419-430. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch34
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Image of Figure 8
Figure 8

Sites of modification by resistance enzymes on neomycin.

Citation: Puglisi J, Blanchard S, Dahlquist K, Eason R, Fourmy D, Lynch S, Recht M, Yoshizawa S. 2000. Aminoglycoside Antibiotics and Decoding, p 419-430. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch34
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Image of Figure 9
Figure 9

Molecular contacts between rRNA and mRNA in the A site may discriminate between cognate and near-cognate tRNAs. (A) A1492 and A1493 (N-1) positions interact with the phosphodiester backbone of the A-site mRNA, which forms an A-form helix with the cognate codon. These specific contacts drive conformational signaling between ribosomal subunits. (B) For near-cognate (or noncognate) tRNAs, the helix formed between the mRNA and tRNA is distorted by base mispairs. The distorted helix is poorly recognized by A1492 and A1493, and this results in poor conformational signaling during decoding.

Citation: Puglisi J, Blanchard S, Dahlquist K, Eason R, Fourmy D, Lynch S, Recht M, Yoshizawa S. 2000. Aminoglycoside Antibiotics and Decoding, p 419-430. In Garett R, Douthwaite S, Liljas A, Matheson A, Moore P, Noller H (ed), The Ribosome. ASM Press, Washington, DC. doi: 10.1128/9781555818142.ch34
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