Protein synthesis inhibitor

Mechanism

In general, protein synthesis inhibitors work at different stages of bacterial mRNA translation into proteins, like initiation, elongation (including aminoacyl tRNA entry, proofreading, peptidyl transfer, and bacterial translocation) and termination:

Earlier stages

• Rifamycin inhibits bacterial DNA transcription into mRNA by inhibiting DNA-dependent RNA polymerase by binding its beta-subunit.
• alpha-Amanitin is a powerful inhibitor of eukaryotic DNA transcription machinery.

Initiation

• Linezolid acts at the initiation stage, probably by preventing the formation of the initiation complex, although the mechanism is not fully understood.

Ribosome assembly

• Aminoglycosides prevent ribosome assembly by binding to the bacterial 30S ribosomal subunit.

Aminoacyl tRNA entry

• Tetracyclines and Tigecycline{{cite journal | access-date = 2009-12-19 | url-access = subscription

Proofreading

• Aminoglycosides, among other potential mechanisms of action, interfere with the proofreading process, causing increased rate of error in synthesis with premature termination.

Peptidyl transfer

• Chloramphenicol blocks the peptidyl transfer step of elongation on the 50S ribosomal subunit in both bacteria and mitochondria.
• Macrolides (as well as inhibiting ribosomal translocation and other potential mechanisms) bind to the 50s ribosomal subunits, inhibiting peptidyl transfer.
• Streptogramins such as Quinupristin/dalfopristin act synergistically, with dalfopristin, enhancing the binding of quinupristin, as well as inhibiting peptidyl transfer.Page 212 in: Title: Hugo and Russell's pharmaceutical microbiology Authors: William Barry Hugo, Stephen P. Denyer, Norman A. Hodges, Sean P. Gorman Edition: 7, illustrated Publisher: Wiley-Blackwell, 2004 Length: 481 pages Quinupristin binds to a nearby site on the 50S ribosomal subunit and prevents elongation of the polypeptide, as well as causing incomplete chains to be released.
• Geneticin, also called G418, inhibits the elongation step in both prokaryotic and eukaryotic ribosomes.
• Trichothecene mycotoxins are potent and non selective inhibitors of peptide elongation.

Ribosomal translocation

• Macrolides, and aminoglycosides (with all these three having other potential mechanisms of action as well), have evidence of inhibition of ribosomal translocation.
• Fusidic acid prevents the turnover of elongation factor G (EF-G) from the ribosome.
• Ricin inhibits elongation by enzymatically modifying an rRNA of the eukaryotic 60S ribosomal subunit.

Termination

• Macrolides{{cite journal
• Puromycin has a structure similar to that of the tyrosinyl aminoacyl-tRNA. Thus, it binds to the ribosomal A site and participates in peptide bond formation, producing peptidyl-puromycin. However, it does not engage in translocation and quickly dissociates from the ribosome, causing a premature termination of polypeptide synthesis.
• Streptogramins also cause premature release of the peptide chain.

Protein synthesis inhibitors of unspecified mechanism

• Retapamulin
• Mupirocin
• Fusidic acid

Binding site

The following antibiotics bind to the 30S subunit of the ribosome:

• Aminoglycosides
• Tetracyclines

The following antibiotics bind to the 50S ribosomal subunit:

• Chloramphenicol
• Clindamycin
• Linezolid (an oxazolidinone)
• Macrolides
• Telithromycin
• Streptogramins
• Retapamulin

References

References

1. Frank Lowy. "Protein Synthesis Inhibitors".
2. "7.344 Antibiotics, Toxins, and Protein Engineering, Spring 2007". MIT OpenCourseWare.
3. (December 1998). "The Oxazolidinone Linezolid Inhibits Initiation of Protein Synthesis in Bacteria". Antimicrob. Agents Chemother..
4. (October 2008). "Rχ-01, a New Family of Oxazolidinones That Overcome Ribosome-Based Linezolid Resistance". Antimicrobial Agents and Chemotherapy.
5. (2003). "Neomycin and Paromomycin Inhibit 30S Ribosomal Subunit Assembly in Staphylococcus aureus". Current Microbiology.
6. Flavio Guzmán. (2008-08-12). "Protein synthesis inhibitors: aminoglycosides mechanism of action animation. Classification of agents". Pharmamotion.
7. [https://web.archive.org/web/20081226204524/http://pharmamotion.com.ar/protein-synthesis-inhibitors-macrolides-mechanism-of-action-animation-classification-of-agents/ Protein synthesis inhibitors: macrolides mechanism of action animation. Classification of agents] Pharmamotion. Author: Gary Kaiser. The Community College of Baltimore County. Retrieved on July 31, 2009
8. "Geneticin". Thermo Fisher Scientific.
9. (1999). "Trichothecene Mycotoxins Trigger a Ribotoxic Stress Response That Activates c-Jun N-terminal Kinase and p38 Mitogen-activated Protein Kinase and Induces Apoptosis". Journal of Biological Chemistry.
10. [[clindamycin]][http://sitemaker.umich.edu/mc3/clindamycin Wisteria Lane cases → CLINDAMYCIN] {{Webarchive. link. (2012-07-18 University of Michigan. Retrieved on July 31, 2009)
11. (October 1988). "Ricin binding and protein synthesis inhibition in human hematopoietic cell lines". Blood.
12. (June 1988). "Ricin and alpha-sarcin alter the conformation of 60S ribosomal subunits at neighboring but different sites". Eur. J. Biochem..
13. [http://www.drugbank.ca/drugs/DB01256 Drugbank.ca > Showing drug card for Retapamulin (DB01256)] Update Date: 2009-06-23
14. (2008). "Review of medical microbiology and immunology". McGraw-Hill Medical.