Macrolide antibiotics protein synthesis

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. 

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. 

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. 

Pharmacology Telithromycin belongs to the ketolide class of antibacterials and is structurally related to the macrolide family of antibiotics. Telithromycin blocks protein synthesis by binding to domains II and V of 23S rRNA of the 508 ribosomal subunit. Pharmacokinetics ... 

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... 

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). 

An interesting exception to the absolute validity of the tifth postulate is the considerable activity of chloramphenicol derivatives in cell-free model systems of protein synthesis when these derivatives are substituted with amino acyl residues instead of with dichloroacetyl as is the antibiotic itself (rev. in 2°)). This has been traced to the necessity of the dichloroacetyl grouping in aiding in the permeation of the antibiotic through the bacterial envelope 21 The amino acyl derivatives have very low antibacterial activity 20. Permeation failures of actinomycin D, macrolides and distamycin A with respect to certain families of bacteria occlude the action of these antibiotics on their intracellular drug receptors and target reactions but can be overcome experimentally by measures which render test organisms permeable. 

More than 500 different representatives of the macrolide antibiotics are known, most of which are biologically active against Gram-positive bacteria, displaying a relatively low toxicity. Clinically used are erythromycin, oleandomycin, carbomycin and leucomycin (O Fig. 5). They act as inhibitors of the bacterial protein biosynthesis by binding to the 50S-ribosomal subunit. The synthesis of the two clinically important 16-membered ring macrolide antibiotics leucomycin A3 and carbomycin B could be started from D-glucose, which was chosen because it contained three of the required stereocenters [40]. 

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). 

Macrolides inhibit growth of bacteria by inhibiting protein synthesis on ribosomes (17,415,416). Bacterial resistance to macrolides is often accompanied by cross-resistance to lincosamide and streptogramin B antibiotics (MLS-resistance), which can be either inducible or constitutive (417). 14-Membered macrolides generally induce resistance to themselves, whereas 16-membered macrolides do not consequendy, one advantage of the latter is their activity against bacteria which are inducibly resistant to erythromycin. Both 14- and 16-membered macrolides lack activity against constitutively resistant strains (387,388). 

The aminoglycosides are bacteriocidal. Other antibiotics whose mechanism of action involves inhibition of protein synthesis (tetracycline, the macrolides, lincomycin, etc.) are invariably bacteriostatic. The reason for this difference is not known. In fact, the reason that protein inhibition by aminoglycosides should be a cell-killing process has not been satisfactorily addressed. The accumulation of nonsense proteins due to misreading of mRNA has been shown not to be the reason. If ribosomal binding were an irreversible process, lethality might be comprehensible SM does not bind irreversibly. 

Clindamycin binds exclusively to the 50S subunit of bacterial ribosomes and suppresses protein synthesis. Although clindamycin, erythromycin, and chloramphenicol are not structurally related, they act at sites in close proximity, and binding by one of these antibiotics to the ribosome may inhibit the interaction of the others. There are no clinical indications for the concurrent use of these antibiotics. Macrolide resistance due to ribosomal methylation by encoded enzymes also may produce resistance to clindamycin. However, because cUndamycin does not induce the methylase, there is cross-resistance only if the enzyme is produced con-stitutively. Clindamycin is not a substrate for macrolide efflux pumps thus, strains that are resistant to macrolides by this mechanism are susceptible to clindamycin. Altered metabolism occasionally causes clindamycin resistance. 

Erythromycin is a macrolide/ophthalmic/otic/topical antibiotic that interferes with microbial protein synthesis. 

Angiolam A (88) is a 19-membered ring macrolide lactam antibiotic produced by a myxobacterium, Angiococcus disciformis [111]. It inhibited protein synthesis. 

It is widely accepted that MLS antibiotics inhibit protein synthesis by binding to closely related sites on the 508 subunit of the 70S ribosome of bacteria [4], despite being structurally different from each other (see Figs. 1 and 2 in a later section). That is the reason why, when inducible resistant Staphylococcus aureus cells are exposed to a low concentration of the drug (0.05 tg erythromycin/ml - 6.8 x 10 M), they show resistance against not only erythromycin but also other macrolide antibiotics as well as lincosamide and type B streptogramin antibiotics. Erythromycin has been widely used and has been the object of extensive molecular and biological studies. 

Observation of the inhibition of protein synthesis [5] and increased macrolide accumulation [6, 9] due to the binding of the antibiotics to ribosome prompted researchers to investigate more detailed mechanisms of the actions of drugs. Many well-organized reviews on the action mechanisms of the drugs have been published from thel960s until the 1990s [2, 3, 10-19]. 

It is well known that nonprotonated molecules of a macrolide antibiotic are the active species of an inhibitor of protein synthesis [39], In our experimental condition (pH 7.6), nonprotonated molecules of rokitamycin can be calculated to be about 10 times as numerous as those of erythromycin from values of 7.6 and 8.7, respectively (Table I) [34]. Despite having the advantage in the number of nonprotonated molecules, the ratio of rokitamycin bound per ribosome (41%) is only about half as much as that of bound erythromycin (76%), when the molecules of the antibiotics each are incubated with the same amount of ribosome molecules. This suggests that rokitamycin s mode of binding to ribosomes may be noticeably different from that of erythromycin. 

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