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
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