Lincosamides

Lincosamides are a class of antibiotics, which include lincomycin, clindamycin, and pirlimycin. Lincosamides are a class of antibiotics, which include lincomycin, clindamycin, and pirlimycin. Lincosamides consist of pyrrolidine ring linked to a pyranose moiety (methylthio-lincosamide) via an amide bond. Hydrolysis of lincosamides, specifically lincomycin, splits the molecule into its building blocks of the sugar and proline moieties. Both of these derivatives can conversely be recombined into the drug itself or a derivative. Biosynthesis of lincosamides occurs through a biphasic pathway, in which propylproline and methylthiolincosamide are independently synthesized immediately before condensation of the two precursor molecules. Condensation of the propylproline carboxyl group with the methylthiolincosamide amine group via an amide bond forms N-demethyllincomycin. N-Demethyllincomycin is subsequently methylated via S-adenosyl methionine to produce lincomycin A. Lincomycin is naturally produced by bacteria species, namely Streptomyces lincolnensis, S. roseolus, and S. caelestis. Clindamycin is derived via (7S)-chloro-subtitution of the (7R)-hydroxyl group of lincomycin. Lincomycin is primarily isolated from fermentations of Streptomyces lincolnensis, while clindamycin is prepared semi-synthetically. While several hundred synthetic and semi-synthetic derivatives of lincosamides have been prepared, only lincomycin A and clindamycin are used in clinical practice due to issues with toxicity and low biological activity in other lincosamide antibiotics. Lincosamides prevent bacterial replication in a bacteriostatic mechanism by interfering with the synthesis of proteins. In a mechanism similar to macrolides and streptogramin B, lincosamides bind close to the peptidyl transferase center on the 23S portion of the 50S subunit of bacterial ribosomes. High resolution X-ray structures of clindamycin and ribosomal subunits from bacterium have previously revealed exclusive binding to the 23s segment of the peptidyl transferase cavity. Binding is mediated by the mycarose sugar moiety which has partially overlapping substrates with peptidyl transferase. By extending to the peptidyl transferase center, lincosamides cause the premature dissociation of peptidyl-tRNA's containing two, three or four amino acid residues. In this case, peptides will grow to a certain point until steric hindrance inhibits peptidyl transferase activity. Lincosamides do not interfere with protein synthesis in human cells (or those of other eukaryotes) due to structural differences between prokaryotic and eukaryotic ribosomes. Lincosamides are used against Gram positive bacteria since they are unable to pass through the porins of Gram-negative bacteria. Soon after the emergence of clinical lincosamide use in 1953, strains of resistant staphylococci were isolated in several countries including France, Japan and the United States. Resistant strains were characterized by expression of methyltransferases which demethylate residues within the 23S subunit of ribosomal RNA, preventing binding of macrolides, lincosamides and streptogramins B. The gene family responsible for encoding of these methyltransferases is referred to as the 'erm' family, or erythromycin ribosome methylase family of genes. Nearly 40 erm genes have been reported to date, which are transferred primarily through plasmids and transposons. Several strains of bacteria which are highly resistant to macrolide treatment have been isolated and found to possess mutations at the transferase binding pocket in the 23S ribosomal subunit. Macrolide resistant Pneumococci isolated from hospital patients in Eastern Europe an North America were found to contain mutations in either 23S or other ribosomal protein genes. Gram-negative bacteria harbor genes encoding for molecular pumps which can contribute to resistance of hydrophobic compounds like macrolides and lincosamides. Out of the many families of multidrug resistance pumps, lincosamides are most commonly shunted through pumps belonging to the resistance-nodulation-cell division superfamily. Staphylococci express efflux pumps with specificity for 14 and 15 member ring macrolides and streptogramin B, but not lincosamide molecules.