Inhibitors of Protein Synthesis

Protein synthesis means translation into a peptide chain of a genetic message first copied (transcribed) into m-RNA (p. 274). Amino acid (AA) assembly occurs at the ribosome. Delivery of amino acids to m-RNA involves different transfer RNA molecules (t-RNA), each of which binds a specific AA. Each t-RNA bears an "anticodon" nucleobase triplet that is complementary to a particular m-RNA coding unit (codon, consisting of 3 nucleobases.

Incorporation of an AA normally involves the following steps (A):

1. The ribosome "focuses" two codons on m-RNA; one (at the left) has bound its t-RNA-AA complex, the AA having already been added to the pep-tide chain; the other (at the right) is ready to receive the next t-RNA-AA complex.

2. After the latter attaches, the AAs of the two adjacent complexes are linked by the action of the enzyme pep-tide synthetase (peptidyltransferase). Concurrently, AA and t-RNA of the left complex disengage.

3. The left t-RNA dissociates from m-RNA. The ribosome can advance along the m-RNA strand and focus on the next codon.

4. Consequently, the right t-RNA-AA complex shifts to the left, allowing the next complex to be bound at the right.

These individual steps are susceptible to inhibition by antibiotics of different groups. The examples shown originate primarily from Streptomyces bacteria, some of the aminoglycosides also being derived from Micromonospora bacteria.

1a. Tetracyclines inhibit the binding of t-RNA-AA complexes. Their action is bacteriostatic and affects a broad spectrum of pathogens.

1b. Aminoglycosides induce the binding of "wrong" t-RNA-AA complexes, resulting in synthesis of false proteins. Aminoglycosides are bactericidal. Their activity spectrum encompasses mainly gram-negative organisms. Streptomycin and kanamycin are used predominantly in the treatment of tuberculosis.

Note on spelling: -mycin designates origin from Streptomyces species; -mi-cin (e.g., gentamicin) from Micromonospora species.

2. Chloramphenicol inhibits peptide synthetase. It has bacteriostatic activity against a broad spectrum of pathogens. The chemically simple molecule is now produced synthetically.

3. Erythromycin suppresses advancement of the ribosome. Its action is predominantly bacteriostatic and directed against gram-positve organisms. For oral administration, the acid-labile base (E) is dispensed as a salt (E. stearate) or an ester (e.g., E. succinate). Erythromycin is well tolerated. It is a suitable substitute in penicillin allergy or resistance. Azithromycin, clarithromycin, and roxithromycin are derivatives with greater acid stability and better bioavailability. The compounds mentioned are the most important members of the macrolide antibiotic group, which includes josamycin and spiramycin. An unrelated action of erythromycin is its mimicry of the gastrointestinal hormone motiline ( f interprandial bowel motility).

Clindamycin has antibacterial activity similar to that of erythromycin. It exerts a bacteriostatic effect mainly on gram-positive aerobic, as well as on anaerobic pathogens. Clindamycin is a semisynthetic chloro analogue of lin-comycin, which derives from a Strepto-myces species. Taken orally, clindamy-cin is better absorbed than lincomycin, has greater antibacterial efficacy and is thus preferred. Both penetrate well into bone tissue.

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Ribosome CI

Amino acid

Peptide chain

Doxycycline nh2 ho_nh2

Doxycycline

Peptide chain nh2 ho_nh2

Insertion of "-(hOyCo-O-OH incorrect h0 1 I

amino acid h2n^^nh2 ch2oh nh2

Tobramycin

Aminoglycosides

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