Protein synthesis inhibition lincomycin

Mechanism of Action. THie earliest studies on the mechanism of action of lincomycin showed that lincomycin had the immediate effect on Staphjlococcus aureus of complete inhibition of protein synthesis (23). TThis inhibition results from the blocking of the peptidyltransferase site of the SOS subunit of the bacterial ribosome (24). Litde effect on DNA and RNA synthesis was observed. 

Lincosamides (lincomycin and clindamycin) are representatives of a very small group of drugs synthesized up of an amino acid bound to an amino sugar. Lincosamides bind with the 50 S ribosomal subunit of bacteria and inhibit protein synthesis. They also inhibit pep-tidyltransferase action. Lincosamides are bacteriostatic antibiotics however, when they reach a certain level in the plasma, they also exhibit bactericidal action against some bacteria. Lincosamides are highly active against anaerobic infections such as Peptococcus, Peptostreptococcus, Actinomyces, Propionibacterium, and Clostridium fringens, a few types of Peptococcus and Clostridium. 

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. 

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. 

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. 

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. 

Lincomycin, an antibiotics produced by Streptomyces lincolnensis, has been used widely in the treatment of infections caused by gram positive organisms. Lincomycin inhibited microbial protein synthesis by interacting strongly and specifically with the 50 S ribosomal subunit at mutually related sites. The results show that such interaction was not influenced by any of the chemical modifications of lincomycin structure. One molecule of antibiotic bound per 50 S subunit. It inhibited peptide bond formation, a mixture of protein synthesis which was catalyzed by a peptidyl transferase centre on the 50 S subunit. It interfered with substrate binding at the P- or A- site on the catalytic centre. It probably bound to the ribosome in positions at or close to the peptide transferase centre. 

Lincomycin increased the TEM - 2 fl - lactamase activity of Escherichia Coli (E. Coli) K -12 cells carrying plasmid RP4 at a concentration which slightly inhibited cell growth (70). In a control culture, a lactamase activity reached its maximal level in late log phase, where as when lincomycin was present, a - lactamase activity continued to increase into the stationary phase. Lincomycin (100 pgftnl) inhibited both cell growth and protein synthesis by about 35 % but the activity of stimulated o lactamase was 2.5 fold per ml of culture and about 4 - fold per cell after 20 hours of growth. Inactivation oh b lactamase appeared to be faster when lincomycin was present. This was determined by measuring the decrease ip b lactamase activity when phenethyl alcohol was present to prevent maturation of the enzyme. 

Gryaznova et al (73) studied the effect of lincomycin on metabolism of Actinomyces reseolus producing lincomycin. The results show that lincomycin inhibited protein synthesis by 50 % at 1000ug/l. When mycelio were cultured for 24 69 hours, their sensitivity to lincomycin decreased. 

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. 

Lincomycin, which resembles erythromycin, in a dose of 500 mg t.i.d., is indicated in the treatment of serious infections due to susceptible strains of streptococci, pneumococci, and staphylococci resistant to other antibiotics. Lincomycin inhibits protein synthesis by interfering with the formation of initiation complexes and with aminoacyl translocation reactions. The receptor for lincomycins on the 50S subunit of the bacterial ribosome is a 23S rRNA, perhaps identical to the receptor for erythromycins (see also Figure 88). Thus, these two drug classes may block each other s attachment and may interfere with each other. Resistance to lincomycin appears slowly, perhaps as a result of chromosomal mutation. Plasmid-mediated resistance has not been established with certainty. Resistance to lincomycin is not rare among streptococci, pneumococci, and staphylococci. C. difficile strains are regularly resistant. 

A. Classification and Pharmacokinetics The lincosamides lincomycin and clindamycin inhibit bacterial protein synthesis via a mechanism similar to that of the macrolides, though they are not chemically related. Mechanisms of resistance include methylation of the binding site on the 50S ribosomal subunit and enzymatic inactivation. Cross-resistance between lincosamides and macrolides is common. Good tissue penetration occurs after oral absorption. The lincosamides are eliminated partly by metabolism and partly by biliary and renal excretion. 

Chloramphenicol is a bacteriostatic agent that binds to the 508 ribosomal subunit and inhibits the transpeptidation in protein synthesis. While this agent is not widely used to treat staphylococcal infection, resistance to chloramphenicol is due to inactivation of the antibiotic by chloramphenicol acetyltransferase enzyme (CA7). Macrolides, such as erythromycin and oleandomycin lincosamides, such as lincomycin and clindamycin and streptogramin antibiotics also have a bacteriostatic effect on Staphylococcus spp. by binding to their 508 ribosomal subunit, arresting protein synthesis, but resistance to these antibiotics is also prevalent. Rifampin has also been used to treat staphylococcal infections, but when used alone, resistant strains quickly arise. 

The clinically important antibiotic lincomycin [1, 2] exerts its antibacterial activity by the inhibition of protein synthesis at the ribosomal level. A study of the structure of lincomycin by Hoeksema and co-workers [3] employing both classical chemical degradation and nuclear magnetic resonance data, led to the announcement of the structure of the molecule. Lincomycin proved to be a member of a new class of antibiotics characterized by an alkyl 6-amino-6,8-dideoxy-l-thio-D-erythro OL-D-galacto-octopymno- side joined with the proline moiety by an amide linkage (Fig. 1). 

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