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Chapter 4 : Antibiotics That Block Bacterial Protein Biosynthesis

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Abstract:

This chapter deals with the various classes of antibiotics that exert their bacteriostatic or bactericidal action by blockade of one or more of the protein biosynthetic steps that occur on the 30S and 50S subunits of the bacterial ribosome. It presents a summary on the ribosome and then analyzes the sites and mechanism of action of ribosome-inhibiting antibiotics. The peptidyl chain is translocated onto the aminoacyl-tRNA in the A site by the peptidyltransferase activity in each peptide-chain-elongation cycle of the ribosome. Architectural differences in the 23S RNA of bacterial ribosomes versus their eukaryotic counterparts provide selectivity for killing of the bacteria. The recent X-ray analysis of macrolide antibiotics bound to bacterial ribosomes gives some insight into this selectivity. The determination of the structure of the 30S ribosomal subunit from with bound drug has revealed a major binding site and a lower-affinity binding site for tetracycline. Aminoglycosides are potent drugs against gram-negative bacteria but not very effective against gram-positive organisms, although the combination of aminoglycosides and β-lactams is used to treat enterococcal infections. It has been reported that linezolid-resistant mutants map to the 23S rRNA sites near the peptidyltransferase center, consistent with recent kinetic studies showing that oxazolidinones are competitive inhibitors of both A-site and P-site substrates.

Citation: Walsh C. 2003. Antibiotics That Block Bacterial Protein Biosynthesis, p 51-69. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch4

Key Concept Ranking

Bacterial Proteins
1.2926986
Antibiotics
0.594502
Hygromycin B
0.51739997
Protein Biosynthesis
0.51305574
1.2926986
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Untitled

Antibiotics that block bacterial protein biosynthesis.

Citation: Walsh C. 2003. Antibiotics That Block Bacterial Protein Biosynthesis, p 51-69. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch4
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Image of Color Plate 4.1
Color Plate 4.1

Interaction of 30S and 50S subunits and location of tRNAs in the A site, P site, and E site. (A) The ribosome 30S subunit is shown on the left, the 50S subunit is at right. (B) 908 rotation from (A) shows the back of the 50S subunit and the location of the exit tunnel for the nascent polypeptide chain. (C) View of the 50S subunit from the 50S/30S subunit interface with tRNAs in P, A, and E sites. (D) View of the 30S subunit interface. (From Yusupov et al. [2001] with permission.)

Citation: Walsh C. 2003. Antibiotics That Block Bacterial Protein Biosynthesis, p 51-69. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch4
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Image of Color Plate 4.2
Color Plate 4.2

(A) Threading of the mRNA into the 30S subunit decoding region; (B) placement of the A, P, and E codons of the mRNA in the decoding site; (C) architecture of a tRNA highlighting the anti-codon loop that recognizes the codons on mRNA and the CCA tail where the amino acid is covalently tethered and activated. (From Culver [2001] with permission.)

Citation: Walsh C. 2003. Antibiotics That Block Bacterial Protein Biosynthesis, p 51-69. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch4
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Image of Figure 4.1
Figure 4.1

Schematic of peptide bond formation at the ribosome.

Citation: Walsh C. 2003. Antibiotics That Block Bacterial Protein Biosynthesis, p 51-69. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch4
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Image of Color Plate 4.3
Color Plate 4.3

The peptidyl transferase center on the 50S ribosomal subunit. (A) Docking of the CCdAp-puromycin complex at the peptidyl transferase center of the 50S subunit; (B) two-dimensional projection of the interaction of CCdAp-puromycin with A2486 and analogous geometry of the tetrahedral intermediate during peptide bond formation at the same site on the ribosome.

Citation: Walsh C. 2003. Antibiotics That Block Bacterial Protein Biosynthesis, p 51-69. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch4
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Image of Color Plate 4.4
Color Plate 4.4

The polypeptide exit tunnel through the 50S ribosome.

Citation: Walsh C. 2003. Antibiotics That Block Bacterial Protein Biosynthesis, p 51-69. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch4
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Image of Figure 4.2
Figure 4.2

Steps in binding, codon recognition, GTPase activation, proofreading, and peptidyl transfer in peptide bond formation. (Modified from Rodnina and Wintermeyer [2001].)

Citation: Walsh C. 2003. Antibiotics That Block Bacterial Protein Biosynthesis, p 51-69. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch4
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Image of Figure 4.3
Figure 4.3

Structures of some antibiotics that act at (A) the 30S subunit or (B) the 50S subunit of bacterial ribosomes.

Citation: Walsh C. 2003. Antibiotics That Block Bacterial Protein Biosynthesis, p 51-69. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch4
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Image of Color Plate 4.5a
Color Plate 4.5a

Mode of action of macrolide antibiotics: (A) binding of macrolides at the 50S polypeptide exit tunnel; (B) interaction with the 23S RNA bases; (C) overlap with the binding sites for clindamycin and chloramphenicol as well as the A-site and P-site tRNAs; (D) inventory of the molecules that are overlapped in panel C. In direct assays of peptidyl transferase activity, erythromycin does not block activity. (From Nissen et al. [2000] with permission.)

Citation: Walsh C. 2003. Antibiotics That Block Bacterial Protein Biosynthesis, p 51-69. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch4
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Image of Color Plate 4.5b
Color Plate 4.5b

Mode of action of macrolide antibiotics: (A) binding of macrolides at the 50S polypeptide exit tunnel; (B) interaction with the 23S RNA bases; (C) overlap with the binding sites for clindamycin and chloramphenicol as well as the A-site and P-site tRNAs; (D) inventory of the molecules that are overlapped in panel C. In direct assays of peptidyl transferase activity, erythromycin does not block activity. (From Nissen et al. [2000] with permission.)

Citation: Walsh C. 2003. Antibiotics That Block Bacterial Protein Biosynthesis, p 51-69. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch4
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Image of Figure 4.4
Figure 4.4

Structures of the pristinamycin I (quinuprustin) and pristinamycin IIA (dalfopristin) components of the peptide antibiotic Synercid.

Citation: Walsh C. 2003. Antibiotics That Block Bacterial Protein Biosynthesis, p 51-69. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch4
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Image of Figure 4.5
Figure 4.5

Structures of tetracycline, chlortetracycline, oxytetracycline, doxycycline, a glycylcycline (DMG-MINO), and tigilcycline.

Citation: Walsh C. 2003. Antibiotics That Block Bacterial Protein Biosynthesis, p 51-69. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch4
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Image of Color Plate 4.6
Color Plate 4.6

(A) Binding site for tetracycline with 16S rRNA on the 30S bacterial subunit of the ribosome; (B) interactions of tetracycline with helix 34 of 16S RNA. (From Schlunzen et al. [2001] with permission.)

Citation: Walsh C. 2003. Antibiotics That Block Bacterial Protein Biosynthesis, p 51-69. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch4
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Image of Figure 4.6
Figure 4.6

Aminoglycoside antibiotics: tobramycin, amikacin, and hygromycin B.

Citation: Walsh C. 2003. Antibiotics That Block Bacterial Protein Biosynthesis, p 51-69. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch4
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Image of Color Plate 4.7
Color Plate 4.7

Binding site for (A) the aminoglycoside hygromycin B and (B) streptomycin with the 16S rRNA of the 30S ribosomal subunit.

Citation: Walsh C. 2003. Antibiotics That Block Bacterial Protein Biosynthesis, p 51-69. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch4
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