The Structural Basis for the Action of the Antibiotics Tetracycline, Pactamycin, and Hygromycin B on the 30S Ribosomal Subunit

Brodersen, D.E.; Clemons, William M.; Carter, Andrew P.; Morgan-Warren, Robert J.; Wimberly, Brian T.; Ramakrishnan, V.

doi:10.1016/s0092-8674(00)00216-6

Cited by 831 publications

(800 citation statements)

References 58 publications

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“…This complex then binds reversibly to the A site on the head of the 30S subunit (Figure 18). 96, 97 This binding site has a slight overlap with the anticodon stem‐loop, which correlates well with previous observations that tetracycline prevents binding of the aforementioned aa‐tRNA ⋅ EF‐Tu ⋅ GTP ternary complex to the A site 98…”

Section: Protein Synthesis Inhibitorssupporting

confidence: 89%

“…Co‐crystal structures of a variety of bound aminoglycosides have been published, including with streptomycin ( 31 , PDB ID: 1FJG),110 spectinomycin ( 32 , PDB ID: 1FJG),110 hygromycin B ( 33 , PDB ID: 1HNZ),97 neomycin B ( 34 , PDB ID: 4V52),111 paromomycin ( 35 , PDB ID: 1FJG, 1IBK),110, 112 tobramycin ( 36 , PDB ID: 1LC4),113 and kanamycin A ( 37 , PDB ID: 2ESI) 109…”

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

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Targeting Antibiotic Resistance

2016

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Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.

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Section: Protein Synthesis Inhibitorssupporting

confidence: 89%

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

Targeting Antibiotic Resistance

2016

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“…24,25 These studies suggest that the 970 loop plays an important role in protein synthesis. This notion is supported by structural studies showing that the 970 loop forms part of the primary binding site for tetracycline 26,27 and by the isolation of a tetracycline-resistant strain of Helicobacter pylori that contains three mutations at positions 965, 966 and 967. 28 Here, we identify the sequence and structural motifs of the 970 loop nucleotides that are essential for ribosome function in bacteria and propose a model for the role of the 970 loop in protein synthesis.…”

Section: Introductionmentioning

confidence: 89%

Identification and role of functionally important motifs in the 970 loop of Escherichia coli 16S ribosomal RNA

Saraiya¹,

Lamichhane

Chow

et al. 2008

Journal of Molecular Biology

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SummaryThe 970 loop (helix 31) of Escherichia coli 16S rRNA contains two modified nucleotides, m 2 G966 and m 5 C967. Positions A964, A969 and C970 are conserved among the Bacteria, Archaea and Eukarya. The nucleotides present at positions 965, 966, 967, 968 and 971, however, are only conserved and unique within each domain. All organisms contain a modified nucleoside at position 966, but the type of the modification is domain specific. Biochemical and structure studies have placed this loop near the P site and have shown it to be involved in the decoding process and in binding the antibiotic tetracycline. To identify the functional components of this rRNA hairpin, the eight nucleotides of the 970 loop of helix 31 were subjected to saturation mutagenesis and 107 unique functional mutants were isolated and analyzed. Non-random nucleotide distributions were observed at each mutated position among the functional isolates. Nucleotide identity at positions 966 and 969 significantly affects ribosome function. Ribosomes with single mutations of m 2 G966 or m 5 C967 produce more protein in vivo than wild-type ribosomes. Over-expression of initiation factor 3 (IF3) specifically restored wild-type levels of protein synthesis to the 966 and 967 mutants, suggesting that modification of these residues is important for IF3 binding and for the proper initiation of protein synthesis.

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“…Finally, it is important to mention that the oxygen atoms of the keto-carbonyl and hydroxyl groups seem to play a major role in the antibacterial activity of tetracycline (1), although the complete mechanism is not known so far [46]. The oxidation products 2 and 3 can probably exhibit a similar (or even higher) activity than that of 1 since these critical sites, i.e., the oxygen atoms of the keto-carbonyl and hydroxyl groups, are preserved in their structures.…”

Section: Ozonation Of Tetracycline: Mechanism and Product Structuresmentioning

confidence: 99%

Monitoring the degradation of tetracycline by ozone in aqueous medium via atmospheric pressure ionization mass spectrometry

Dalmázio

Almeida

Augusti

et al. 2007

J. Am. Soc. Mass Spectrom.

160

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The degradation of tetracycline (1) by ozone in aqueous solution was investigated. High performance liquid chromatography (HPLC), UV-visible spectroscopy (UV-Vis), and total organic carbon (TOC) analyses revealed that although tetracycline was quickly consumed under this oxidative condition, it did not mineralize at all. Continuous monitoring by electrospray ionization mass spectrometry in the positive ion mode, ESI(ϩ)-MS, revealed that tetracycline (1), detected in its protonated form ([1 ϩ H] ϩ ) of m/z 445, reacted to yield almost exclusively two unprecedented oxidation products (2 and 3) via a net insertion of one and two oxygen atoms, respectively. Compound 2, suggested to be formed via an initial 1,3-dipolar cycloaddition of ozone at the C11a-C12 double-bond of 1, and Compound 3, proposed to be produced via a subsequent ozone attack at the C2-C3 double-bond of 2, were detected in their protonated forms in the ESI(ϩ)-MS, i.e.,

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The Structural Basis for the Action of the Antibiotics Tetracycline, Pactamycin, and Hygromycin B on the 30S Ribosomal Subunit

Cited by 831 publications

References 58 publications

Targeting Antibiotic Resistance

Targeting Antibiotic Resistance

Identification and role of functionally important motifs in the 970 loop of Escherichia coli 16S ribosomal RNA

Monitoring the degradation of tetracycline by ozone in aqueous medium via atmospheric pressure ionization mass spectrometry

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