Superiority of 11,12 Carbonate Macrolide Antibiotics as Inhibitors of Translation and 50S Ribosomal Subunit Formation in Staphylococcus aureus Cells

1999 ◽  
Vol 38 (6) ◽  
pp. 342-348 ◽  
Author(s):  
W. Scott Champney ◽  
Craig L. Tober
Keyword(s):  
Staphylococcus Aureus ◽  
Ribosomal Subunit ◽  
Macrolide Antibiotics

scholarly journals 50S ribosomal subunit synthesis and translation are equivalent targets for erythromycin inhibition in Staphylococcus aureus.

1996 ◽  
Vol 40 (5) ◽  
pp. 1301-1303 ◽  
Author(s):  
W S Champney ◽  
R Burdine
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Growth ◽  
Growth Rates ◽  
Bacterial Cell ◽  
Direct Relationship ◽  
Ribosomal Subunit ◽  
Inhibitory Effect ◽  
Macrolide Antibiotics ◽  
Bacterial Cells ◽  
Subunit Assembly

Macrolide antibiotics like erythromycin can prevent the formation of the 50S ribosomal subunit in growing bacterial cells, in addition to their inhibitory effect on translation. The significance of this novel finding has been further investigated. The 50% inhibitory doses of erythromycin for the inhibition of translation and 50S subunit assembly in Staphylococcus aureus cells were measured and were found to be identical. Together they account quantitatively for the observed effects of erythromycin on cell growth rates. There is also a direct relationship between the loss of rRNA from the 50S subunit and its accumulation as oligoribonucleotides in cells. The importance of this second site for erythromycin inhibition of bacterial cell growth is discussed.

scholarly journals The Structures of Four Macrolide Antibiotics Bound to the Large Ribosomal Subunit

2002 ◽  
Vol 10 (1) ◽  
pp. 117-128 ◽  
Author(s):  
Jeffrey L. Hansen ◽  
Joseph A. Ippolito ◽  
Nenad Ban ◽  
Poul Nissen ◽  
Peter B. Moore ◽  
...  
Keyword(s):  
Ribosomal Subunit ◽  
Macrolide Antibiotics ◽  
Large Ribosomal Subunit

scholarly journals Retapamulin Inhibition of Translation and 50S Ribosomal Subunit Formation in Staphylococcus aureus Cells

2007 ◽  
Vol 51 (9) ◽  
pp. 3385-3387 ◽  
Author(s):  
W. Scott Champney ◽  
Ward K. Rodgers
Keyword(s):  
Staphylococcus Aureus ◽  
16S Rrna ◽  
Cell Viability ◽  
Protein Biosynthesis ◽  
Ribosomal Subunit ◽  
Inhibitory Effect ◽  
23S Rrna ◽  
Specific Inhibition ◽  
Methicillin Resistant

ABSTRACT Retapamulin inhibited protein biosynthesis and cell viability in methicillin-sensitive and methicillin-resistant Staphylococcus aureus organisms. A specific inhibitory effect on 50S ribosomal subunit formation was also found. Pulse-chase labeling experiments confirmed the specific inhibition of 50S subunit biogenesis. Turnover of 23S rRNA was found, with no effect on 16S rRNA amounts.

scholarly journals Structural insights into species-specific features of the ribosome from the pathogen Staphylococcus aureus

2015 ◽  
Vol 112 (43) ◽  
pp. E5805-E5814 ◽  
Author(s):  
Zohar Eyal ◽  
Donna Matzov ◽  
Miri Krupkin ◽  
Itai Wekselman ◽  
Susanne Paukner ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Staphylococcus Aureus ◽  
Ribosomal Subunit ◽  
Binding Modes ◽  
Large Ribosomal Subunit ◽  
Structural Motifs ◽  
Antibiotic Drugs ◽  
Species Specific ◽  
Structural Insights ◽  
Shed Light

The emergence of bacterial multidrug resistance to antibiotics threatens to cause regression to the preantibiotic era. Here we present the crystal structure of the large ribosomal subunit from Staphylococcus aureus, a versatile Gram-positive aggressive pathogen, and its complexes with the known antibiotics linezolid and telithromycin, as well as with a new, highly potent pleuromutilin derivative, BC-3205. These crystal structures shed light on specific structural motifs of the S. aureus ribosome and the binding modes of the aforementioned antibiotics. Moreover, by analyzing the ribosome structure and comparing it with those of nonpathogenic bacterial models, we identified some unique internal and peripheral structural motifs that may be potential candidates for improving known antibiotics and for use in the design of selective antibiotic drugs against S. aureus.

scholarly journals Abstract P-26: Staphylococcus Aureus 30S Ribosomal Subunit in a Complex with the Era GTPase: Sample Preparation for Cryo-EM

2021 ◽  
Vol 11 (Suppl_1) ◽  
pp. S23-S23
Author(s):  
Evelina Klochkova ◽  
Aydar Bikmullin ◽  
Shamil Validov ◽  
Natalia Garaeva ◽  
Marat Yusupov ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Ribosome Biogenesis ◽  
Pathogenic Bacteria ◽  
Rna Binding ◽  
Ribosomal Subunit ◽  
Precise Determination ◽  
Amino Acid Sequences ◽  
Multifunctional Protein ◽  
Final Sample

Background: An essential in bacteria GTPase Era is a multifunctional protein that is involved in cell cycle regulation and appears to play a significant role in ribosome biogenesis. It is required for the maturation of the 30S ribosomal subunit. Era consists of two domains: the GTPase N-terminal domain, conserved in the GTPase family, and a C-terminal RNA-binding KH domain. Era specifically binds to the 16S rRNA and stimulates processing of the small ribosomal subunit to its mature form. Precise determination of nucleotide and amino acid sequences in the active site of binding will help in finding specific ways to prevent this interaction. In this way, it will be possible to disrupt the biogenesis of the ribosome and, thereby, stop or slow down protein synthesis in the bacterial cell. It is very important in the fight against pathogenic bacteria, such as Staphylococcus aureus (S. aureus). Methods: The His-tagged Era (His–Era) protein from S. aureus was expressed in E. coli BL21 strain and purified by Ni-NTA and SEC. The 30S ribosomal subunits were collected after dissociation of the S. aureus 70S ribosomes in sucrose gradient (0 – 30%). Complex 30S-Era was obtained by mixing in vitro 30S subunits and His–Era, incubated for 15 min at 37°C and followed by Ni-NTA purification to remove unbound 30S subunits. The presence of a stable 30S-Era complex has been confirmed by SDS-PAGE and agarose gel electrophoresis. The final sample quality was analyzed by negative staining EM. Results: For the first time in vitro 30S-Era complex from S. aureus was assembled and a sample was prepared for further structural studies by cryo-electron microscopy.

scholarly journals Solithromycin Inhibition of Protein Synthesis and Ribosome Biogenesis in Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae

2013 ◽  
Vol 57 (4) ◽  
pp. 1632-1637 ◽  
Author(s):  
Ward Rodgers ◽  
Ashley D. Frazier ◽  
W. Scott Champney
Keyword(s):  
Staphylococcus Aureus ◽  
Protein Synthesis ◽  
Streptococcus Pneumoniae ◽  
Haemophilus Influenzae ◽  
Ribosome Biogenesis ◽  
Antimicrobial Agents ◽  
Protein Biosynthesis ◽  
Ribosomal Subunit ◽  
23S Rrna ◽  
Content Type

ABSTRACTThe continuing increase in antibiotic-resistant microorganisms is driving the search for new antibiotic targets and improved antimicrobial agents. Ketolides are semisynthetic derivatives of macrolide antibiotics, which are effective against certain resistant organisms. Solithromycin (CEM-101) is a novel fluoroketolide with improved antimicrobial effectiveness. This compound binds to the large 50S subunit of the ribosome and inhibits protein biosynthesis. Like other ketolides, it should impair bacterial ribosomal subunit formation. This mechanism of action was examined in strains ofStreptococcus pneumoniae,Staphylococcus aureus, andHaemophilus influenzae. The mean 50% inhibitory concentrations (IC50s) for solithromycin inhibition of cell viability, protein synthesis, and growth rate were 7.5, 40, and 125 ng/ml forStreptococcus pneumoniae,Staphylococcus aureus, andHaemophilus influenzae, respectively. The net formation of the 50S subunit was reduced in all three organisms, with IC50s similar to those given above. The rates of 50S subunit formation measured by a pulse-chase labeling procedure were reduced by 75% in cells growing at the IC50of solithromycin. Turnover of 23S rRNA was stimulated by solithromycin as well. Solithromycin was found to be a particularly effective antimicrobial agent, with IC50s comparable to those of telithromycin and significantly better than those of azithromycin and clarithromycin in these three microorganisms.

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