Chemistry and mode of action of macrolides.
After the discovery of erythromycin and other natural compounds, including oleandomycin, spiramycin, josamycin and midecamycin, much research has been devoted to synthesizing derivatives or analogues with improved chemical, biological and pharmacokinetic properties. These new macrolides are semisynthetic molecules that differ from the original compounds in their substitution pattern of the lactone ring system. The chemical structure of macrolides is characterized by a large lactone ring containing from 12 to 16 atoms to which are attached, via glycosidic bonds, one or more sugars. The lactone ring is substituted by hydroxyl or alkyl groups, one ketone at C7 in 12-membered macrolides and at C9 in 14-membered macrolides, and one aldehyde group in 16-membered macrolides. The only compound with a 15-membered ring contains a tertiary amino group. Although the 12-membered macrolides have never become important in clinical practice, in recent years numerous new 14-membered macrolide derivatives of erythromycin A have shown improved pharmacokinetics due to chemical modifications of a hydroxyl group at C6, a proton at C8, or a ketone at C9. Derivatives, such as dirithromycin, roxithromycin, clarithromycin and flurithromycin, have all been synthesized with the aim of inhibiting their decomposition under acidic conditions to inactive anhydrohemiketal derivatives. A new 15-membered macrolide, azithromycin, with a methylated nitrogen inserted into the lactone ring shows good activity against Gram-negative bacteria. The efforts expended in chemical and biochemical modifications of 16-membered macrolides have been less successful, with only a few new molecules, such as rokitamycin and miocamycin, showing improved bioavailability and activity against some resistant micro-organisms.(ABSTRACT TRUNCATED AT 250 WORDS)
Mazzei
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T
Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
Mini
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E
Novelli
A
A
Periti
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P
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D001426:Bacterial Proteins / Q000096:biosynthesis; D018942:Macrolides; D012329:RNA, Bacterial / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012343:RNA, Transfer / Q000378:metabolism; D012346:RNA, Transfer, Amino Acyl / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D018942:Macrolides; D012329:RNA, Bacterial; D012333:RNA, Messenger; D012346:RNA, Transfer, Amino Acyl; C019037:tRNA, peptidyl-; D012343:RNA, Transfer