Inhibition of Escherichia coli ribosome subunit dissociation by chloramphenicol and Blasticidin: a new mode of action of the antibiotics.

Abstract

The ability of the ribosome to assist in folding of proteins both in vitro and in vivo is well documented and is a nontranslational function of the ribosome. The interaction of the unfolded protein with the peptidyl transferase centre (PTC) of the bacterial large ribosomal subunit is followed by release of the protein in the folding competent state and rapid dissociation of ribosomal subunits. Our study demonstrates that the PTC-specific antibiotics, chloramphenicol and blasticidin S inhibit unfolded protein-mediated subunit dissociation. During post-termination stage of translation in bacteria, ribosome recycling factor (RRF) is used together with elongation factor G to recycle the 30S and 50S ribosomal subunits for the next round of translation. Ribosome dissociation mediated by RRF and induced at low magnesium concentration was also inhibited by the antibiotics indicating that the PTC antibiotics exert an associative effect on ribosomal subunits. In vivo, the antibiotics can also reduce the ribosomal degradation during carbon starvation, a process requiring ribosome subunit dissociation. This study reveals a new mode of action of the broad-spectrum antibiotics chloramphenicol and blasticidin.

SIGNIFICANCE AND IMPACT OF THE STUDY:

Ribosome synthesizes protein in all organisms and is the target for multiple antimicrobial agents. Our study demonstrates that chloramphenicol and blasticidin S that target the peptidyl transferase centre of the bacterial ribosome can then inhibit dissociation of 70S ribosome mediated by (i) unfolded protein, (ii) translation factors or (iii) low Mg+2 concentrations in vitro and thereby suppresses ribosomal degradation during carbon starvation in vivo. The demonstration of this new mode of action furthers the understanding of these broad-spectrum antibiotics that differentially inhibit protein synthesis in prokaryotic and eukaryotic cells.

• Authors: B K Pathak, S Mondal, C Barat
• Journal: Letters in applied microbiology (Lett Appl Microbiol) Vol. 64 Issue 1 Pg. 79-85 (Jan 2017) ISSN: 1472-765X [Electronic] England
• PMID: 27739094 (Publication Type: Journal Article)
• Copyright: © 2016 The Society for Applied Microbiology.

Chemical References

• Anti-Bacterial Agents
• Nucleosides
• Peptide Elongation Factor G
• Prokaryotic Initiation Factor-3
• Protein Synthesis Inhibitors
• Ribosomal Proteins
• ribosome releasing factor
• Chloramphenicol
• blasticidin S
• Peptidyl Transferases

Topics

• Anti-Bacterial Agents (pharmacology)
• Chloramphenicol (pharmacology)
• Crystallography, X-Ray
• Escherichia coli (drug effects)
• Nucleosides (pharmacology)
• Peptide Elongation Factor G
• Peptidyl Transferases (antagonists & inhibitors)
• Prokaryotic Initiation Factor-3
• Protein Binding
• Protein Synthesis Inhibitors (pharmacology)
• Ribosomal Proteins (antagonists & inhibitors)
• Ribosome Subunits (drug effects, metabolism, ultrastructure)