The lincomycins are sulfur-containing antibiotics isolated from Streptomyces lincolnensis. Lincomycin is the most active and medically useful of the compounds obtained from fermentation. Extensive efforts to modify the lincomycin structure to improve its antibacterial and pharmacological properties resulted in the preparation of the 7-chloro-7-deoxy derivative clindamycin. Of the two antibiotics, clindamycin appears to have the greater antibacterial potency and better pharmacokinetic properties. Lincomycins resemble macrolides in antibacterial spectrum and biochemical mechanisms of action. They are primarily active against Grampositive bacteria, particularly the cocci, but are also effective against non-spore-forming anaerobic bacteria, actino-mycetes, mycoplasma, and some species of Plasmodium. Lincomycin binds to the 50S ribosomal subunit to inhibit protein synthesis. Its action may be bacteriostatic or bactericidal depending on various factors, including the concentration of the antibiotic. A pattern of bacterial resistance and cross-resistance to lincomycins similar to that observed with the macrolides has been emerging.195
Lincomycin hydrochloride (Lincocin), which differs chemically from other major antibiotic classes, was isolated by Mason et al.220 Its chemistry was described by Hoeksema et al.221 who assigned the structure, later confirmed by Slomp and MacKellar,222 given in the diagram below. Total syntheses of the antibiotic were accomplished independently in 1970 in England and the United States.223,224 The structure contains a basic function, the pyrrolidine nitrogen, by which water-soluble salts with an apparent pKa of 7.6 may be formed. When subjected to hydrazinolysis, lincomycin is cleaved at its amide bond into trans-l-4-n-propylhygric acid (the pyrrolidine moiety) and methyl a-thiolincosamide (the sugar moiety). Lincomycin-related antibiotics have been reported by Argoudelis225 to be produced by S. lincolnensis. These antibiotics differ in structure at one or more of three positions of the lincomycin structure: (a) the N-methyl of the hygric acid moiety is substituted by a hydrogen; (b) the n-propyl group of the hygric acid moiety is substituted by an ethyl group; and (c) the thiomethyl ether of the a-thiolin-cosamide moiety is substituted by a thioethyl ether.
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