Antibiotics targeting the 50S ribosomal subunit
Macrolides, chloramphenicol and fusidic acid disturb the ribosomal subunit 50S function and have antibiotic properties.
Macrolides have a macrocyclic lactone ring, usually of 14 or 16 atoms, to which are attached deoxy-sugars. The drug of reference of this group is erythromycin. Many other macrolides spiramycin, midecamycin, josamycin, roxithromycin, dirithromycin have been marketed but are little used now. Clarithromycin and azithromycin, semisynthetic derivatives of erythromycin with a broader spectrum are the most used. .
Macrolides inhibit protein synthesis by binding to the ribosomal subunit 50S rRNA, more precisely the 23S rRNA part.
They penetrate into bacteria in non ionized form which predominates at alkaline pH. Gram-positive bacteria accumulate approximately 100 times more erythromycin than gram-negative organisms, which explains its predominant action on Gram-positive microorganisms.
The macrolides have a bacteriostatic or bactericidal activity depending on their concentration and the sensitivity of the microorganisms. They are active against cocci Gram-positive aerobic and anaerobic, Gram-negative cocci like gonococci and meningococci, Gram negative bacilli like Helicobacter pylori, and microorganisms like Legionella pneumophilia, Mycoplasma, Clamydia. But resistance to macrolides via different mechanisms extends and reduces their clinical efficacy, many strains of pneumococci are resistant.
Concerning pharmacokinetics, it should be noted that erythromycin can be inactivated by the acid gastric fluid and must be administered with enteric coating. Erythromycin inhibits the inactivation of several drugs such as ergotamine, carbamazepine, cyclosporine, cisapride, digoxin, warfarin, bromocriptine, astemizole. This inhibition can induce important rises in the plasma concentration of these drugs when they are taken at the same time and cause adverse effects sometimes severe, as those which were observed with ergotamine.
Clarithromycin (Klaricid*, Biaxin*) is used in the treatment of various infections: sinusitis, bronchitis, pneumopathy and at higher dosage in the treatment of infections with Mycobacterium avium in patients infected by HIV and for the eradication of Helicobacter pylori. The catabolism of clarithromycin is dose-related, which means that its concentration in the body increases more strongly than the increase of its dosage.
Azithromycin (Zithromax*) is used for the treatment of otitis, sinusitis and pneumopathies, and in monodose for clamydial urethritis.
The main adverse effects of macrolides are allergic: fever, eruption, eosinophilia, and, especially after parenteral administration, tinnitus, hearing loss as observed with aminoglycosides. Digestive symptoms such as diarrhea observed during treatments with erythromycin are generally not the consequence of its antibiotic effect but of its capacity to release motilin or to activate motilin receptors. Derivatives of erythromycin without antibiotic effect could stimulate intestinal motility and treat constipation.
Synergystins, lincosanides and telithromycin, are usually related to the macrolide group.
Synergystins, also called streptogramins, are pristinamycin and virginiamycin, the latter is not marketed any more. They have a relatively broad spectrum of action but are especially used in the treatment of staphylococcal infections. Pristinamycin can cause allergic reactions and sometimes severe skin lesions.
Quinupristin-dalfopristin (Synercid*) is a combination of two semisynthetic antibiotics derived from pristinamycin, acting on the 50S ribosomal subunit. The combination is administered by parenteral route. It is active against Gram-positive microorganisms like staphylococci, pneumococci and enterococci resistant to methicillin and vancomycin.
Lincosanides, clindamycin and lincomycin, have a spectrum of action similar to that of erythromycin but a better activity against anaerobic bacteria. They have similar properties, but clindamycin could be more active. The main adverse effect of lincosamides is pseudomembranous colitis, sometimes serious, caused by Clostridium difficile, which can be treated by vancomycin or metronidazole.
Telithromycin (Ketek*), is a semi-synthetic product related to macrolides but classified among ketolides because it involves ketone functions. It is used in the treatment of pneumonia, bronchitis and acute sinusitis; it can also be used in the treatment of pharyngitis caused by group A beta hemolytic streptococci. It can lengthen the QT interval and is contraindicated in patients having a long QT interval or a bradycardia. It inhibits the cytochrome CYP 3A4 leading to many possible drug interactions. It can give various reversible ocular disorders and sometimes severe hepatic damage.
Chloramphenicol has a broad-spectrum bacteriostatic activity. It is active against the majority of Gram-negative organisms, Salmonella typhi, Brucella, and against Gram-positive cocci like Clostridium.
It inhibits protein synthesis by binding to the 50S subunit of the bacterial ribosome on a site close to but different from that of clindamycin and macrolides. It prevents the addition of an amino-acyl-tRNA to the incipient polypeptide chain. Resistance to chloramphenicol results from the synthesis by bacteria of acetyltransferase, a plasmid-encoded enzyme inactivating the drug by acetylation.
Concerning pharmacokinetics, chloramphenicol has a good digestive absorption, a broad distribution, a good penetration into the cerebral spinal fluid.
Chloramphenicol (Chloromycetin*) has been replaced by other antibiotics and is only used now for the treatment of infections with organisms resistant to other antibiotics. Is also u sed as an ophthalmic preparation for eye infections
Its main adverse effect, probably by inhibiting protein synthesis in mammal erythropoietic cells, is bone marrow damage with aplastic anemia, agranulocytosis, thrombocytopenia, sometimes fatal. In patients treated by chloramphenicol, a monitoring of blood count is necessary. In premature and newborn infants chloramphenicol has caused the “grey syndrome” with ashen color and signs of profound alteration.
Thiamphenicol, chemically related to chloramphenicol, perhaps better tolerated, has been used in some countries.
Linezolid (Zyvox*), antibiotic of the oxazolidone type, also binds to the subunit 50S. It is active against microorganisms such as staphylococci resistant to other antibiotics. It has, in addition, a reversible, non selective MAOI activity able to cause interactions with drugs inactivated by the MAO enzyme.
Fusidic acid has a steroid structure. It inhibits protein synthesis by binding to the factor of elongation G, EF-G or translocase, coupled to GTPase. It thus prevents the moving of the ribosome along the mRNA.
Fusidic acid exerts at low concentration a bacteriostatic effect, and at a higher concentration a bactericidal effect on Gram-positive microorganisms, in particular Staphylococcus aureus. It is inactive on gram-negative organisms.
Fusidic acid (Fucidine*, Fucithalmic*) is used as antistaphyloccic in combination with an aminoglycoside or a beta-lactamine and as an ophthalmic preparation.
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