Lincomycin synthesis

Sinkula, A. A., Ma-ozowich, W., Rowe, E. L. Chemical modifications of lincomycin synthesis and bioactivity of selected 2,7-dialkylcatbonate esters. 7. Pharrru ScL 1973,62,1106-1 111. 

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. 

Golebiowski A., Jurczak J. Total Synthesis of Lincomycin and Related Chemistry... 

Lincomycins bacteriostatic activity is based on the inhibition of the bacterial proteic synthesis. Lincomycin A in particular have been largely employed in clinical therapy of infections caused by micoplasmas, Gram-positive bacteria, and cocci but it presents a lot of side effects overcome by 7-clindamycin (Fig. 21), a semi-synthetic drug with larger spectrum of action and major antibacterial activity. 

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. 

Pharmacology Lincomycin and clindamycin, known collectively as lincosamides, bind exclusively to the 50 S subunit of bacterial ribosomes and suppress protein synthesis. Cross-resistance has been demonstrated between these 2 agents. Clindamycin is preferred because it is better absorbed and more potent. Pharmacokinetics Administration with food markedly impairs lincomycin (but not clindamycin) oral absorption. 

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. 

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... 

Compounds such as puromycin and cycloheximide, which block rRNA transfer, and streptomycin and lincomycin, which cause misreading of messenger RNA (mRNA), block protein synthesis and are therefore often embryolethal. 

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. 

A. Gotebiowski and J. Jurczak, Total synthesis of lincomycin and related chemistry. Recent Progress in the Chemical Synthesis of Antibiotics, (G. Lukacs and M. Ohno, eds.). Springer Verlag, Heidelberg, 1990, p. 365. 

The Synthesis of N-Acetyl-lincosamine (6-Acetamido-6,8-dideoxy-D-ert/fhro-D-ga-lacto-octose), a Derivative of the Free Carbohydrate Moiety in Lincomycin, G. B. Howarth, W. A. Szarek, and J. K. N. Jones, Chem. Commun., (1969) 1339-1340. 

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. 

The two established members of the group of antibiotics known as the hncosamides, lincomycin and its semisynthetic derivative chndamycin, have a narrow antibacterial spectrum involving mostly Gram-positive species and some obhgate anerobes, such as Bacteroides. Like chloramphenicol and erythromycin, they combine with a subunit of bacterial ribosomes and interfere with protein synthesis. 

R, D. Birkenmeyer and F. Kagan, Lincomycin. XI. Synthesis and structure of clindamycin, a potent antibacterial agent, J. Med. Chem. 13 616 (1970). 

Stereocontrolled lincomycin was synthesized from methyl - D galactopyranoside, I, of methyl thio -lincosa - minide, II, using the direct synthesis precursor to lincomycin (5). The off - pyranose stereocenters C - 6 and C - 7 were controlled by an intramolecular nitrogen delivery reaction using epoxy alcohol. 

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. 

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