Lincosaminides

The discovery and biological properties of lincomycin (1, R = OH, R = H) were described ia 1962 (1). This antibiotic is active in vitro and in vivo against most of the common gram-positive pathogens. Resistance by Staphylococci is developed slowly ia a stepwise manner, based on in vitro serial subculture experiments, and its activity is not iafluenced by body fluids up to concentrations of 50% ia the assay medium (2). 

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. 

Resistance to Lincomycin. Resistance to lincomycin is developed slowly, and is usually caused by modification of 23S ribosomal RNA, which leads to co-resistance to macroHde, lincosaminide, and streptogramin B antibiotics (25). Inactivation of lincomycin by clinical isolates of strains of Staphjlococcus aureus and Staphjlococcus haemoljticus, though retention of sensitivity to macroHdes (see Antibiotics, macrolides) and streptogramins (see Antibiotics, peptides), has been found to be the consequence of the conversion of the antibiotic into its 3-(5 -adenylate) (26). 

Pharmacology and Uses. Lincomycin hydrochloride (Lincocin) is available in oral dosage forms and as a sterile solution for injection. After 

Kirk-Othmer Encyclopedia of Chemical Technology (4th Edition) 

Lincomycin [154-21-2] (1, R = OH, R = H), C. H N O. S, the first lincosaminide antibiotic to which a structure was assigned, is defined chemically as methyl 6,8-dideoxy-6-(1-methyl-/n7/7X-4-propyl-L-pyrrolidin-2-ylcarbonylamino)-l-thio-D-erythro-E-galacto-octopyranoside. Both lincomycin and the semisynthetic clindamycin [18525-44-9] (1, R = H, R = Q), C1,H33ON2 O 5S, are widely used in clinical practice. The trivial name of the sugar fragment of this antibiotic, methyl a-thiolincosaminide, has lent itself to the other members of this family, whether produced as secondary metabolites of soil 

Biosynthesis. The terminal C-methyl of the propyl side chain, the L-methyl, and the ZV-methyl groups are derived from methionine (19). /ftmf-4-Propyl-L-proline [51101-27-6] was shown to accumulate when Streptomyces lincolnensis is grown in media deficient in sulfur, and the addition of L-tyrosine or L-dihydroxyphenylalanine (DOPA) was shown to stimulate this production. From a comparison of the incorporation of label from L-[l-14C]tyrosine and l[U-14C tyro sine, it was demonstrated that all of the carbon atoms of the propylproline other than the C-terminal methyl group were derived from tyrosine and, by the use of L-[15N]tyrosine, it was determined that the proline nitrogen atom was derived from the amino—nitrogen atom of tyrosine (20). 

---