Protein synthesis inhibition macrolides

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,... 

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. 

Pharmacology Macrolide antibiotics reversibly bind to the P site of the SOS ribosomal subunit of susceptible organisms and inhibit RNA-dependent protein synthesis. They may be bacteriostatic or bactericidal, depending on such factors as drug concentration. 

Macrolides and lincosamides have the same receptor site. They bind to the bacterial 50s ribosomal subunit, inhibiting protein synthesis and hence cell growth. Macrolides are usually bacteriostatic at low concentrations, but can become bactericidal for sensitive strains at high concentrations. 

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. 

Mechanism of Action A macrolide that binds to ribosomal receptor sites of susceptible organisms, inhibiting protein synthesis of the bacterial cell wall. Therapeutic Effect Bacteriostatic maybe bactericidal with high dosages or very susceptible microorganisms. 

Mecfianism of Action A macrolide that reversiblybindstobacterial ribosomes, inhibiting bacterial protein synthesis. Therapeutic Effect Bacteriostatic. Pharmacokinetics Variably absorbed from the GI tract (depending on dosage form used). Protein binding 70%-90%. Widely distributed. Metabolized in the liver. Primarily eliminated in feces by bile. Not removed by hemodialysis. Half-life 1.4-2 hr (increased in impaired renal function). 

The glycoside/aminoglycoside antibiotics, like the macrolides, exert a bacteriostatic effect due to selective inhibition of bacterial protein synthesis, with the exception of novobiocin (26). The compounds neomycin (27), spectinomycin (28) and streptomycin (29) bind selectively to the smaller bacterial 30S ribosomal subunit, whilst lincomycin (30) binds to the larger 50S ribosomal subunit (cf. macrolides). Apramycin (31) has ribosomal binding properties, but the exact site is uncertain (B-81MI10802). Novobiocin (26) can inhibit nucleic acid synthesis, and also complexes magnesium ion, which is essential for cell wall stability. 

Macrolides inhibit growth of bacteria by inhibiting protein synthesis on ribosomes. Bacterial resistance to macrolides is often accompanied by cross-resistance to lincosamide and sireptogramin B antibiotics (MLS-resistance), which can be either inducible or constitutive. 14-Membered... 

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. 

Although these compounds are all anticancer agents, they act through different mechanisms. Bryostatin 1, a cyclic macrolide, inhibits protein kinase C tumor promotion while aplidine is a protein synthesis inhibitor. Dolastatin 10, a linear peptide, and ET743, a tetrahydroisoquinoline... 

The macrolides bind irreversibly to a site on the 50S subunit of the bacterial ribosome, thus inhibiting the translocation steps of protein synthesis. Generally considered to be bacteriostatic, they may be cidal at higher doses. The binding site is either identical to or in close proximity to that for lincomycin, clindamycin, and chloramphenicol. 

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). 

Macrolides inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and preventing elongation of the peptide chain. These drugs have low toxicity because they do not bind to mammalian ribosomes. 

Peloruside A (31), which is a 16-membered, highly oxidized macrolide from the sponge Mycale hentscheli, induces tubulin polymerization (2). 13-Deoxytedanolide (32) isolated from Japanese sponges of the genus Mycale shows promising antitumor activity. It inhibits protein synthesis by binding to a 70 S large subunit of eukaryotic ribosome (17). 

The mode of action of macrolide antibiotics involves the inhibition of protein synthesis of specific binding to the 50S ribosomal subunit but without a specific target at the 23S ribosomal subunit and various proteins [66]. Nevertheless, the exact interaction of the macrolide and the ribosome unit is still not fully understood. In principle, the macrolide antibiotic should inhibit also mammalian mitochondrial protein syuithesis but they are unable to penetrate the mitochondrial membrane. 

The MLS (macrolides, lincosamides, streptogramins) group of antibiotics all inhibit protein synthesis by binding to the 50S ribosomal subunit. Resistance mechanisms specific to individual members occur but resistance to all may be conferred by a single mechanism that involves 23S rRNA. However, it is claimed that the quinupristin-dalfopristin combination does not demonstrate cross-resistance to other antibiotics within the MLS group or to other antibiotics. 

Examples of antibiotics that attack bacteria by inhibiting protein synthesis at the ribosomal level include the following tetracycline antibiotics (e.g. chlortetracycline) aminoglycoside antibiotics (e.g. neomycin, streptomycin) macrolide antibiotics (e.g. erythromycin, clarithromycin, azithromycin) also chloramphenicol, fusidic acid and lincosamides (e.g. clindamycin). 

Inhibition of protein synthesis through an action on certain subunits of microbial ribosomes (aminoglycosides, tetracyclines, chlorampenicol and its derivatives, macrolides and lincosamides). Each class of antimicrobial agent attaches to a different receptor site apart from macrolides and lincosamides, which bind to the same site on the 50S subunit of the microbial ribosome. 

Inhibition of bacterial protein synthesis Aminoglycosides, chloramphenicol, macrolides, tetracyclines, streptogramins, linezolid... 

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