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Inhibitors of protein synthesis

Antibacterial Agents II

Reference
Katzung, B.G. Basic and Clinical Pharmacology, Eighth Edition, Chapters 44 and 45, p774-783.

Cast of characters
Aminoglycosides (streptomycin, amikacin, tobramycin, neomycin, etc.),
Spectinomycin
Chloramphenicol
Clindamycin
Tetracycline (and minocycline, doxycycline, etc.)
Erythromycin (and azithromycin)
Fusidic acid
Linezolid
All of the agents discussed in this lecture are inhibitors of bacterial protein synthesis.

Clinical usage
Given that the penicillins and cephalosporins are the antibacterial agents with the highest
therapeutic index, they are the drugs of first choice all other things being equal. The rationale for
the use of the agents discussed in this lecture are summarized below. All have a lower
therapeutic index compared to the penicillins.
Bacteria
To potentiate the action of penicillins in serious infections (aminoglycosides) CNS infections - (penicillins are weak acids) TB (streptomycin) - slow growing bacteria are resistant to penicillins Selectivity

Inhibition of protein synthesis catalyzed by chloramphenicol clindamycin erythromycin linezolid (fusidic
The target for all these drugs is the polysomes (polyribosomes) in the bacterial cytoplasm.
Depending on the drug, these may or may not be degraded.
Although it might be predicted that the agents above are reasonably selective (i.e., bacterial
versus human), mitochondrial protein synthesis is inhibited by the 70 S specific agents in vitro.
[Fusidic acid has not been approved for use in the USA. Derivatives of it should become
available in the near future.]

Mechanism of action

Aminoglycosides bind to the 30S subunit and block initiation of protein synthesis by forming aberrant initiation complexes. In addition, they cause miscoding at the aminoacyl-tRNA-mRNA step. Chloramphenicol and clindamycin inhibit peptidyl transferase (Note that in your textbook Tetracycline inhibits binding of aminoacyl-tRNAs at the A site. Erythromycin and spectinomycin inhibit translocation. Fusidic acid action results in the formation of a ternary complex in which the drug is bound to the ribosome together with elongation factor G in its ADP-bound state although movement of the tRNA-peptide occurs from the A to the P site. Linezolid binds to 23S RNA of the 50S ribosomal subunit.
Resistance to these agents can occur at several levels.
Resistance can occur by inability to bind to ribosomal proteins and/or RNA.
Some are also inactivated by secreted enzymes, e.g., chloramphenicol acetyl transferase,
adenylylating (and other) enzymes active against many aminoglycosides.
Tetracycline resistance can also occur by pumping the drug out of the cell faster than it gets in.
Side effects (Specific)
Aminoglycosides- nephrotoxicity, ototoxicity
Chloramphenicol- aplastic anemia
Clindamycin- pseudomembranous colitis (Clostridium difficile)
Tetracyclines-chelating agents which are deposited in bones and teeth;
Azithromycin-fewer drug interactions than erythromycin because it doesn't inhibit cytochrome
P450
Study Questions

1.
On the figure describing protein synthesis, indicate where the various classes of agents The following table of information is the basis for the next set of questions. Inhibits a specific initiation step of protein synthesis

Source: http://users.umassmed.edu/martin.marinus/Mph200/Antibacterialagents2.pdf

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