Lactone ring erythromycins

It is a macrolide antibiotic obtained by substitution of hydroxyl group by a CH O group in the erythromycin lactone ring. It is found to be 2 to 10 times more active than erythromycin. 

Many natural products are lactones and it is not unusual to find examples m which the ring size is rather large A few naturally occurring lactones are shown m Figure 19 8 The macrohde antibiotics of which erythromycin is one example are macrocychc (large ring) lactones The lactone ring of erythromycin is 14 membered... 

Another group of antibiotics that can be inactivated by hydrolysis are 14- and 15- membered macrolides [2]. Esterases cleave the lactone ring. The plasmid encoded ere genes are found in members of the Enter-obacteriaceae and increase the intrinsic resistance. Furthermore, these esterases can also be found in some isolates of erythromycin resistant staphylococci. 

Very large ring lactones are called macrolides, and are found in the natural macrolide antibiotics. Typically, these may have 12-, 14-, or 16-membered lactone rings, though other sizes are encountered. Erythromycin is a... 

Spiramycin is another macrolide, recently introduced into medicine for the treatment of toxoplasmosis, infections caused by the protozoan Toxoplasma gondii. This contains a 16-membered lactone ring (erythromycin has a 14-membered ring), and two aminosugars, o-mycaminose and o-forosamine. o-Forosamine is remarkable in having only one hydroxyl group, and that is bound up in the hemiacetal ring system. 

The macrolide antibiotics are those that consist of a large lactone ring to which sugars are attached. Antibiotics in this group include erythromycin (Ilotycin, E-mycin,... 

Azithromycin is an azalide antibiotic, a sub-class of the macrolides. Azithromycin differs chemically from erythromycin in that a methyl substituted nitrogen atom is incorporated into the lactone ring. 

The macrolides are a group of closely related compounds characterized by a macrocyclic lactone ring (usually containing 14 or 16 atoms) to which deoxy sugars are attached. The prototype drug, erythromycin, which consists of two sugar moieties attached to a 14-atom lactone ring, was obtained in 1952 from Streptomyces erythreus. Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin. 

Azithromycin is rapidly absorbed and well tolerated orally. It should be administered 1 hour before or 2 hours after meals. Aluminum and magnesium antacids do not alter bioavailability but delay absorption and reduce peak serum concentrations. Because it has a 15-member (not 14-member) lactone ring, azithromycin does not inactivate cytochrome P450 enzymes and therefore is free of the drug interactions that occur with erythromycin and clarithromycin. 

The macrolides form an important group of clinically useful antibiotics. Older members include erythromycin (6), oleandomycin, triacetyloleando-mycin and spiramycin, now joined by clarithromycin (44), roxithromycin (45) and azithromycin (46) [196]. Enterobacteria which show a high level of insusceptibility to erythromycin can inactivate the antibiotic by plasmid-encoded esterases that hydrolyse the lactone ring [197],... 

The molecular backbone of the antibiotic erythromycin A [6-desoxy-erythronolide B (3)] is built up repetitively from one propionyl-coenzyme A (1) and six methyl-malonyl-coenzyme A (2) constituents by the action of polyketide-synthase, which itself consists of three proteins (DEBS 1 -3) (Schemes 1 and 2). Each protein contains two modules with several separate, cat-alytically active domains. In the first section, DEBS 1 carries an additional loading zone, and DEBS 3 contains a thioesterase in the final segment, catalyzing the decoupling of the product by building the lactone ring [6],... 

Macrolide antibiotics are glycosides with a macrocyclic lactone aglycon, which is formed in the polyketide biosynthetic pathway [38,39]. The lactone ring is 12-, 14-, 16-, or 18-mem-bered. The polyoxo-macrolides such as the classical antibiotic erythromycin are produced by streptomyces microorganisms and form a clinically important group of polyketide antibiotics. Erythromycin (O Fig. 5) is the major component out of a mixture of macrolide antibiotics which is formed by Saccharopolyspora erythraea. It contains two deoxysugars attached to the aglycon, L-cladinose and D-desosamine. 

Lactone ring structure Example Derivative of erythromycin... 

Note The erythromycin molecule was synthesized by the Harvard chemist Robert Woodward. The synthesis was almost completed at the time of his death in 1979, and was finished by his associates in 1981. It is an extremely complex structure containing a lactone ring of 14 members with 10 asymmetric centers it also has two specialized sugar molecules, L-cladinose and D-desosamine. The reported molecular configuration is ... 

The best known example of this class of compounds is erythromycin—a metabolite produced by the microorganism Streptomyces erythreus. The structure (Fig. 10.73) consists of a macrocylic lactone ring with a sugar and an aminosugar attached. The sugar residues are important for activity. 

A few bioconversions of erythromycin have been reported (149). Certain modifications of erythromycin at both its 9-ketone and 11-hydroxyl groups inhibited hydrolysis of the lactone ring by an esterase isolated from Escherichia coli which might be involved in bacterial resistance to macrolides (150). The 9-methoxime-11-[(2-dimethylaminoethyl)oxymethyl] derivative of erythromycin, ER 42859, showed good antibacterial activity and pharmacokinetics in animals, but it gave lower blood levels than erythromycin when administered to humans (151). Other 9,11-cydic derivatives of erythromycin have been synthesized (152,153). Series of 9-A/-alkyl derivatives of both 9(5)- and 9(R)-eiythromycylamine have been prepared which improved activity in vivo over erythromycin (154,155). 

Macrolide antibiotics contain a many-membered lactone ring (14-membered rings for erythromycin and clarithromycin, and a 15-membered ring for azithromycin) to which are attached one or more deoxy sugars. Clarithromycin differs from erythromycin only by methylation of the hydroxyl group at the 6 position, and azithromycin differs by the addition of a methyl-substituted nitrogen atom into the lactone ring. These structural modifications improve acid stability and tissue penetration and broaden the spectrum of activity. 

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