Chemotherapy: antibiotics targeting protein synthesis

44 Chemotherapy


antibiotics targeting protein synthesis





Questions



image How are proteins synthesized in bacteria?

image Which drugs target specific steps of protein synthesis?


Agents affecting protein synthesis


Bacterial protein synthesis occurs on ribosomes, which are made up of two subunits (50S and 30S in bacteria). Messenger RNA (mRNA) is the template for protein synthesis and transfer RNA (tRNA) brings each amino acid to the ribosome for assembly into the protein molecule (Fig. 3.44.1). A number of different classes of drug selectively target different elements of this process. These agents are bacteriostatic, with the exception of aminoglycosides and oxazolidinones.


image

Fig. 3.44.1 Antibiotics acting on protein synthesis.




Tetracyclines


These agents selectively enter bacteria by an uptake process and interfere with protein synthesis by reversibly binding to the 30S subunit, impairing the ability of tRNA to attach to mRNA and thus preventing delivery of an amino acid to the growing peptide chain. Tetracyclines have a broad spectrum of activity, although many strains of bacteria are increasingly becoming resistant. The active concentration of tetracycline within bacteria is reduced by the expression of transporters that pump the antibiotic out of the bacteria. This resistance is transmitted by plasmids and, since the genes that confer resistances are located in close proximity, resistance can also develop to other antibiotics (e.g. sulphonamides). Tetracyclines are orally bioavailable but absorption is impaired by antacids and drinks containing Ca2+ and iron owing to the chelating ability of the tetracyclines. Adverse events include gastrointestinal disturbances and, because of their Ca2+− chelating action, they have a tendency to accumulate in growing bone and teeth. They are best avoided by pregnant women, breastfeeding women and in children.



Aminoglycosides


These agents selectively enter aerobic bacteria by an oxygen-dependent transport system. Hence, anaerobic bacteria have a natural resistance. Aminoglycosides bind to the 30S subunit in an irreversible manner, which leads to misreading of mRNA. These agents have a broad spectrum of activity, with the exception of anerobes, streptococci and pnenumococci. Their bactericidal activity can be enhanced when coadministered with penicillins as damage to the cell wall facilitates penetration of aminoglycosides into the bacteria. Resistance to these drugs is an increasing problem. Aminoglycosides have poor oral bioavailability and are administered i.v. Gentamicin is the aminoglycoside most commonly used to treat infections by Gram-negative bacteria, although tobramycin is preferred for infection with Pseudomonas aeruginosa. Streptomycin is used in the treatment of Mycobacterium tuberculosis. The side-effects of this drug class limit its utility. Adverse events include ototoxicity: a progressive damage to the sensory cells of the cochlea and vestibular organ of the ear resulting in ataxia, loss of balance, vertigo and deafness. Damage to the kidney renal tubules leads to nephrotoxicity, which will impair plasma clearance of the antibiotic. A rare but serious toxic condition is paralysis of skeletal muscle caused by inhibition of Ca2+ uptake into cholinergic nerves and inhibition of release of acetylcholine.


Chloramphenicol is bacteriostatic and binds to the 50S subunit, inhibiting peptidyl transferase activity. This prevents transpeptidation of the growing amino acid chain on the P site to the newly arrived peptidyl tRNA on the A site. This antibiotic has a broad spectrum of activity; however, susceptibility to resistance is high because of expression of ‘chloramphenicol acetyltransferase’. The ability of chloramphenicol to cause aplastic anaemia (decreased production of red blood cells) when administered systemically limits its usefulness and it is reserved for life-threatening infections.

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Jul 18, 2016 | Posted by in PHARMACY | Comments Off on Chemotherapy: antibiotics targeting protein synthesis

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