Biochemistry department

Faculty of medicine

Helwan university

Antibiotics that inhibit protein synthesis

Supervised by / Dr.Dalia Ali
By- Abdelrahman Khaled Fouad
Introduction:

A protein synthesis inhibitor: is a substance that stops or slows the growth or

proliferation of cells by disrupting the processes that lead directly to the generation
of new proteins.[1]
While a broad interpretation of this definition could be used to describe nearly
any antibiotic, in practice, it usually refers to substances that act at
the ribosome level (either the ribosome itself or the translation factor),taking
advantages of the major differences between prokaryotic and eukaryotic ribosome
structures.

Mechanism:

During protein synthesis on the ribosome, the growing peptide is linked covalently to a transfer
RNA.

With a certain probability this peptidyl-tRNA dissociates from the ribosome, whereupon it
becomes susceptible to hydrolysis catalyzed by peptidyl-tRNA hydrolase.

When placed at nonpermissive temperatures, mutant (pthts) Escherichia coli that are temperature-
sensitive for the hydrolase will accumulate peptidyl-tRNA, suffer inhibition of protein synthesis,
and eventually die.

Treating cells with chloramphenicol before raising the temperature prevents cell death but
erythromycin, other macrolides, and lincosamide antibiotics all enhance cell death. Accumulation
of peptidyl-tRNA by pthts cells at high temperatures is blocked by chloramphenicol but enhanced
by macrolides and lincosamides. The data are most consistent with macrolide and lincosamide
antibiotics having as their primary mechanism of inhibition the stimulation of peptidyl-tRNA
dissociation from the ribosome.

Rather than blocking peptide bond formation or peptidyl-tRNA translocation from the A- to the P-
site of the ribosome, these antibiotics allow the synthesis of small peptides which dissociate as
peptidyl-tRNAs before being completed.

Low doses of erythromycin and lincomycin stimulate preferentially the dissociation of peptidyl-
tRNAs that are erroneous. Errors in proteins can be assessed by the time necessary to inactivate
beta-galactosidase at > 55 degrees C.
Whether erroneous peptidyl-tRNAs are induced by treating E. coli with streptomycin or ethanol,
or by starving for an amino acid, the shortened time to inactivate beta-galactosidase is counteracted
if the cells are simultaneously treated with erythromycin or lincomycin.

In contrast, errors in beta-galactosidase caused by synthesis in the presence of canavanine, an

arginine analogue, cannot be counteracted by the simultaneous presence of erythromycin.

This result rules out any effect of the drug on post-translational mechanisms of error correction.
References:

1st paragraph : "Definition: protein synthesis inhibitor from Online Medical Dictionary"

2nd paragraph: https://www.ncbi.nlm.nih.gov/pubmed/8852269

Diagram : http://slideplayer.com/slide/6982122/