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Antibiotics targeting the 30S ribosomal subunit

Inhibitors of 30S ribosomal subunit having antibiotic properties are tetracyclines and aminoglycosides.

Tetracyclines

Tetracyclines of first-generation are tetracycline and oxytretacycline (Terramycin*), those of second-generation, doxycycline (Vibramycin*) and minocycline (Minocin*).

Tetracyclines inhibit protein synthesis by binding to the 30S subunit of ribosomes. They inhibit the binding of the amino-acyl-tRNA to the acceptor site of the mRNA-ribosome complex, which stops protein synthesis by preventing addition of amino acids to the growing peptide.

After passive diffusion or transfer through porin channels of the cell wall of gram-negative organisms, tetracyclines cross the cytoplasmic membrane by active transport, perhaps utilizing a carrier present in certain bacteria.

Tetracyclines have a broad-spectrum bacteriostatic activity, on different Gram-positive and Gram- negative organisms like Rickettsias, Mycoplasmæ, Chlamydiæ, but an acquired resistance is frequent.

They have also, in particular doxycycline, a preventive and curative antimalarial activity by a mechanism poorly understood.

Tetracyclines, and in particular doxycycline, inhibit matrix zinc metalloproteinases which, by hydrolyzing proteins, facilitate the dissemination of cancerous metastases.

Concerning pharmacokinetics, the digestive absorption of tetracyclines like doxycycline and minocycline is close to 100%, on an empty stomach. The presence in the digestive tract of elements such as aluminum, calcium, magnesium, iron or bismuth reduces the digestive absorption of tetracyclines by forming insoluble chelates.

Tetracyclines, which have a great affinity for bone tissue, can induce in children under eight years teeth discoloration or enamel hypoplasia. They can also be the cause of hematologic disorders (thrombocytopenia, neutropenia), phototoxic reactions and digestive disorders (diarrhea, sometimes with Clostridium difficile, hepatitis).

Tetracyclines are contraindicated in pregnant women in late pregnancy, as in women nursing, because there is risk of dental anomalies in children. The risk of hepatic damage could be higher with minocycline than with doxycycline.

Tetracyclines have been used in a sustained way, one to a few months, for the treatment of acne. Doxycycline can be used for the prevention of malaria in case of resistance, contraindication or intolerance to mefloquine.

Tigecycline (Tygacil*) is a new tetracycline active against positive and negative gram microorganisms resistant to traditional tetracyclines. Tigecycline is given twice daily by intravenous route.

Aminoglycosides

The first aminoglycosides were streptomycin and neomycin followed by gentamicin (Garamycin*), amikacin (Amikin*), nétilmicin (Netromycin*), dibekacin, tobramycin (Nebcin*) and isepamicin.

Aminoglycosides are constituted of two or several amino sugars bound by a glycosidic function to a hexose ring. Their amine functions are ionized forming polycations.

Aminoglycosides, bactericidal antibiotics, diffuse into bacteria through porin channels to the periplasmic space. Their penetration through the cytoplasmic membrane is active and requires a supply of energy and the presence of oxygen. When an aminoglycoside is permanently present in contact with a susceptible microorganism, there is an inhibition of its penetration through the cytoplasmic membrane. This observation explains the interest of the discontinuous administration of aminoglycosides

Aminoglycosides disturb the bacterial protein synthesis by binding to the 30S subunit of ribosomes. because of their polycationic character, they displace the magnesium ions. The damage to the bacterial membrane is the consequence of the disturbance of protein synthesis.

Resistance to aminoglycosides can result from a defect of their entry in the bacterial cytoplasm, their inactivation by biotransformations by enzymes, phosphorylase, acetylase, linked to plasmids, a modification of ribosome structure preventing their binding.

Pharmacokinetic characteristics

Aminoglycosides are ionized in the biological environments in the form of polycations, and are not absorbed by the digestive tract, their absorption being lower than 1%.

Their distribution is primarily extracellular: high concentrations are found in the kidney, the endolymph and the perilymph of the internal ear, which explains their renal and cochlear toxicity. The concentration in the cerebral spinal fluid after parenteral administration is low, lower than 10% of that found in plasma.

Their urinary elimination is predominant and they accumulate in the body of patients with renal insufficiency. Insofar as the aminoglycosides do not diffuse in adipose tissue, the adaptation of their dosage could be based on lean body-mass volume.

Only one daily administration instead of two could give a better antibiotic effect with reduced toxicity. The systematic determination of their blood concentrations (peaks, troughs) during treatments can avoid both toxic and insufficient concentrations.

Clinical uses

Aminoglycosides are active against Gram-negative aerobic bacilli, Escherichia coli, Proteus, Kbelsiella pneumonia, pyocyanic bacillus, and on certain Gram-positive microorganisms such as the staphylococcus, but this last becomes resistant, except perhaps to amikacin. They are little or not active against anaerobic microorganisms. Amikacin also has an antituberculous effect.

Streptomycin, which was the first effective antituberculous drug, is usually replaced by rifampicin which inhibits the bacterial RNA polymerase.

Isepamycin is marketed only in some countries.

The antibiotics which damage the wall of bacteria such as beta-lactams reinforce the action of aminoglycosides. On the other hand, certain antibiotics which inhibit protein synthesis, like chloramphenicol, reduce the efficacy of aminoglycosides

Adverse effects

The toxicity of aminoglycosides is primarily renal, cochlear and neuromuscular.

    1. Renal toxicity
      The renal toxicity of aminoglycosides results in a proteinuria and the excretion of enzymes coming from the proximal tubule. The renal damage is generally reversible after the discontinuation of medication. C
      alcium intake could reduce their renal toxicity.
    2. Ototoxicity
      Aminoglycosides can give cochlear and vestibular side effects by damaging the sensory cells, perhaps via the stimulation of NMDA receptors.
    3. Neuro-muscular toxicity

    At the neuromuscular junction, aminoglycosides can reduce acetylcholine release and sensitivity of the nicotinic receptors. apnea can be elicited by the administration of aminoglycosides to patients just after a surgical operation involving the use of neuromuscular blocking agents of D-tubocurarine type.

    Remarks :

    Neomycin has an antibiotic activity similar to that of other aminoglycosides but, because of its toxicity, it is not used by general route. Taken orally, it is little absorbed by the digestive tract and was used for the treatment of infectious diarrheas due to sensitive microorganisms (Escherichia coli, Proteus, Kbelsiella, Enterobacter and bowel preparation before abdominal surgery. It is also used topically to treat mucocutaneous infections.

    Spectinomycin is an aminocyclitol antibiotic, structurally related to aminoglycosides, acting on the 30S subunit of the bacterial ribosome, particularly active against gonococci and used for the treatment of gonorrhea.

    Mupirocin is an antibiotic produced by Pseudomonas fluorescens, active against staphylococci. It inhibits protein synthesis by binding to isoleucyl-tRNA synthetase. It is marketed in the form of nasal preparation, used for eradication of Staphylococcus aureus carriage.

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