Erythromycin, protein synthesis

Erythromycin Streptomyces erythreus Gram-positive bacteria Protein synthesis... 

Ribosomal Protein Synthesis Inhibitors. Figure 5 Nucleotides at the binding sites of chloramphenicol, erythromycin and clindamycin at the peptidyl transferase center. The nucleotides that are within 4.4 A of the antibiotics chloramphenicol, erythromycin and clindamycin in 50S-antibiotic complexes are indicated with the letters C, E, and L, respectively, on the secondary structure of the peptidyl transferase loop region of 23S rRNA (the sequence shown is that of E. coll). The sites of drug resistance in one or more peptidyl transferase antibiotics due to base changes (solid circles) and lack of modification (solid square) are indicated. Nucleotides that display altered chemical reactivity in the presence of one or more peptidyl transferase antibiotics are boxed. 

The macrolide erythromycin inhibits protein synthesis and resistance is induced by N -dimethyl-ation of adenine within the 23S rRNA, which results in reduced affinity of ribosomes for antibiotics related to erythromcin (Skinner et al. 1983). Sulfonamides function by binding tightly to chromosomal dihydropteroate synthetase and resistance to sulfonamides is developed in the resistance plasmid through a form of the enzyme that is resistant to the effect of sulfonamides. 

Macrolides Erythromycin Inhibits protein synthesis by binding Gram-positive cocci, mycoplasma,... 

Newer and more generally usefnl macrolide antibiotics include azithromycin (Zithromax) and clarithromycin (Biaxin). These too are wide-spectrum antibiotics and both are semisynthetic derivatives of erythromycin. Like the tetracyclines, the macrolide antibiotics act as protein synthesis inhibitors and also do so by binding specifically to the bacterial ribosome, thongh at a site distinct from that of the tetracyclines. 

Other key classes of antibacterials include the tetracyclines (Aureomycin, Terramycin), macrolides (erythromycin, Zithromax, Biaxin), and aminoglycosides (streptomycin, amikacin, neomycin). These antibacterials are protein synthesis inhibitors. 

Inhibition of protein synthesis in microorganisms (aminoglycosides, erythromycin, clindamycin, chloramphenicol, and tetracyclines). 

Macrolides, both erythromycin and others, inhibit the synthesis of bacterial proteins. The primary mechanisms of protein synthesis are identical in humans and bacteria. However, there is a significant difference that allows a specific antibiotic to exhibit selective toxicity with respect to bacteria. 

Erythromycin inhibits bacterial protein synthesis by reversibly binding with their 50 S ribosomal subunit, thus blocking the formation of new peptide bonds. Erythromycin is classified as a bacteriostatic antibiotic. 

Anandatheerthavarada, H.K. etal. (1999) Physiological role of the N-terminal processed P4501A1 targeted to mitochondria in erythromycin metabolism and reversal of erythromycin-mediated inhibition of mitochondrial protein synthesis./oumoi of Biological Chemistry, 274 (10), 6617-6625. 

Clindamycin is a chlorine-substituted derivative of lincomycin. However it is more potent and is better absorbed from the gastrointestinal tract and has therefore replaced lincomycin in most situations. Clindamycin is in principle a bacteriostatic agent. Its indications are mainly limited to mixed anaerobic infections. As mentioned above it has a similar mechanism of action as erythromycin. It selectively inhibits bacterial protein synthesis by binding to the same 50s ribosomal subunits. Erythromycin and clindamycin can interfere with each other by competing for this receptor. Also cross-resistance with erythromycin frequently occurs. Resistance is rather chromosomal rather than plasmid mediated and is especially found in cocci and Clostridium difficile. 

Macrolides bind to the SOS ribosomal subunit of bacteria but not to the SOS mammalian ribosome this accounts for its selective toxicity. Binding to the ribosome occurs at a site near peptidyltransferase, with a resultant inhibition of translocation, peptide bond formation, and release of oligopeptidyl tRNA. However, unlike chloramphenicol, the macrolides do not inhibit protein synthesis by intact mitochondria, and this suggests that the mitochondrial membrane is not permeable to erythromycin. 

The lincosamide family of antibiotics includes lin-comycin (Lincocin) and clindamycin (Cleocin), both of which inhibit protein synthesis. They bind to the SOS ri-bosomal subunit at a binding site close to or overlapping the binding sites for chloramphenicol and erythromycin. They block peptide bond formation by interference at either the A or P site on the ribosome. Lincomycin is no longer available for human use in the United States. 

Chloramphenicol (bacteriostatic interrupts protein synthesis at the ribosome) Macrolides (bacteriostatic interrupt protein synthesis at the SOS ribosome subunit) e.g., erythromycin, azithromycin, clarithromycin Lincomycins (bacteriostatic interrupt protein synthesis at the SOS subunit) Aminoglycosides (bactericidal interrupt protein synthesis at the 30S subunit) e.g., gentamicin, amikacin, kanamycin, neomycin, tobramycin Tetracyclines (bacteriostatic interrupt protein synthesis at the 30S subunit) e.g., tetracycline, doxycycline, minocycline... 

It is mainly bacteriostatic and inhibits the growth of gram positive organisms which includes staphylococci, streptococci, pneumococci, C. diphtheriae and B. anthracis. Like erythromycin it act by interfering with protein synthesis. 

Erythromycin Prevents bacterial protein synthesis by binding to the 50S ribosomal subunit Bacteriostatic activity against susceptible bacteria Community-acquired pneumonia t pertussis corynebacterial, and chlamydial infections Oral, IV hepatic clearance (half-life 1.5 h) dosed every 6 h cytochrome P450 inhibitor Toxicity Gastrointestinal upset, hepatotoxicity, QTC prolongation... 

The antibacterial action of erythromycin may be inhibitory or bactericidal, particularly at higher concentrations, for susceptible organisms. Activity is enhanced at alkaline pH. Inhibition of protein synthesis occurs via binding to the 50S ribosomal RNA. Protein synthesis is inhibited because aminoacyl translocation reactions and the formation of initiation complexes are blocked (Figure 44-... 

Like tetracyclines, macrolides are also polyketides that are isolated from bacteria and inhibit protein synthesis in certain bacteria. Erythromycin (A.32) is the original macrolide (Figure A.9). Clarithromycin (Biaxin, A.33) and azithromycin (Zithromax, A.34) are semisynthetic derivatives of erythromycin. 

There are a number of sites within the sequence of protein synthesis where antibiotics can act. These include (1) inhibition of the attachment of mRNA to 30S ribosomes by aminoglycosides (2) inhibition of tRNA binding to 30S ribosomes by tetracyclines (3) inhibition of the attachment of mRNA to the 50S ribosome by chloramphenicol and (4) erythromycin inhibition of the translocation step by binding to 50S ribosomes, thus preventing newly synthesized peptidyl tRNA moving from the acceptor to the donor site. 

Cethromycin (ABT-773) 39 (Advanced Life Sciences) had an NDA filed in October 2008 for the treatment of CAP.67 Advanced Life Sciences is also evaluating cethromycin 39 against other respiratory tract infections and in pre-clinical studies as a prophylactic treatment of anthrax post-exposure. Cethromycin 3968 70 is a semi-synthetic ketolide derivative of erythromycin 4071 originally synthesised by Abbott Laboratories,72 which like erythromycin 40, inhibits bacterial protein synthesis through binding to the peptidyl-transferase site of the bacterial 50S ribosomal subunit. Important macrolide antibiotics in clinical use today include erythromycin 40 itself, clarithromycin, azithromycin and, most recently, telithromycin (launched in 2001). 

A-6) Erythromycin and the tetracyclines. These antibiotics act in part by interfering with bacterial protein synthesis. 

Protein synthesis. Drugs that interfere at various points with the build-up of peptide chains on the ribosomes of the organism include chloramphenicol, erythromycin, fusidic acid, tetracyclines, aminoglycosides, quinupristin/dalfopristin, linezolid. 

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