Macrolide Antibiotics

The macrolide antibiotics are macrocyclic lactones with a ring size typically 12-16 atoms, and with extensive branching through methyl substituents. Two or more sugar units are attached through glycoside linkages, and these sugars tend to be unusual 6-deoxy structures often restricted to this class of compounds. Examples include L-cladinose, L-mycarose, D-mycinose, and L-oleandrose. At least one sugar is an amino sugar, e.g. D-desosamine, D-forosamine, and D-mycaminose. These antibiotics have a narrow spectrum of antibacterial activity, principally against Gram-positive microorganisms. Their antibacterial spectrum resembles, but is not identical to, that of the penicillins, so they provide a valuable alternative for patients allergic to the penicillins. Erythromycin is the principal macrolide antibacterial currently used in medicine.

The erythromycins (Figure 3.65) are macrolide antibiotics produced by cultures of Saccharopolyspora erythraea (formerly Streptomyces erythreus). The commercial product

R1 I OH D-desosamine

O OR2

R1 = OH, R2 = Me, erythromycin A R1 = H, R2 = Me, erythromycin B R1 = OH, R2 = H, erythromycin C

*OH T NMe2

HO | I OH D-desosamine

'OH T NMe2

O' Y O OMe clarithromycin (6-O-methyl erythromycin A)

Figure 3.65

O T o OMe azithromycin

L-cladinose erythromycin is a mixture containing principally erythromycin A, plus small amounts of erythromycins B and C (Figure 3.65). Erythromycin activity is predominantly against Grampositive bacteria, and the antibiotic is prescribed for penicillin-allergic patients. It is also used against penicillin-resistant Staphylococcus strains, in the treatment of respiratory tract infections, and systemically for skin conditions such as acne. It is the antibiotic of choice for infections of Legionella pneumophila, the cause of legionnaire's disease. Erythromycin exerts its antibacterial action by inhibiting protein biosynthesis in sensitive organisms. It binds reversibly to the larger 50S subunit of bacterial ribosomes and blocks the translocation step in which the growing peptidyl-tRNA moves from the aminoacyl acceptor site to the peptidyl donor site on the ribosome (see page 408). The antibiotic is a relatively safe drug with few serious side-effects. Nausea and vomiting may occur, and if high doses are prescribed, a temporary loss of hearing might be experienced. Hepatotoxicity may also occur at high dosage.

Erythromycin is unstable under acidic conditions, undergoing degradation to inactive compounds by a process initiated by the 6-hydroxyl attacking the 9-carbonyl to form a hemiketal. Dehydration then follows (Figure 3.66). The 14-membered ring in erythromycin A adopts a modified version of the diamond lattice chairlike conformation shown in Figure 3.66. Studies have indicated that carbon 6 is displaced from this conformation to reduce the 1,3-diaxial interactions at C-4 and C-6, and the two relatively large sugar units attached to the hydroxyls at C-3 and C-5 also distort the ring system further. The distortion of the chairlike conformation brings the 6-hydroxyl sufficiently close to react with the 9-carbonyl. A similar reaction may occur between the C-12 hydroxyl and the 9-carbonyl. Thus, to protect oral preparations of erythromycin against gastric acid, they are formulated as enteric-coated tablets, or as insoluble esters (e.g. ethyl succinate esters), which are then hydrolysed in the intestine. Esterification typically involves the hydroxyl of the amino sugar desosamine. To reduce this acid instability, semi-synthetic analogues of erythromycin have also been developed. Clarithromycin (Figure 3.65) is a 6-O-methyl derivative of erythromycin A; this modification blocks hemiketal formation as in Figure 3.66. Azithromycin (Figure 3.65) is a ring-expanded aza-macrolide in which the carbonyl function has been reduced. In both analogues, the changes enhance activity compared with that of erythromycin.

Bacterial resistance to erythromycin has become significant and has limited its therapeutic use against many strains of Staphylococcus. Several mechanisms of resistance have been

Hemiketal Macrolide

diamond-lattice conformation

Figure 3.66

diamond-lattice conformation

Figure 3.66

implicated, one of which is a change in permeability of the bacterial cell wall. Differences in permeability also appear to explain the relative insensitivity of Gram-negative bacteria to erythromycin when compared to Gram-positive bacteria. Resistant bacteria may also modify the chemical nature of the binding site on the ribosome, thus preventing antibiotic binding, and some organisms are now known to metabolize the macrolide ring to yield inactive products.

Oleandomycin (Figure 3.62) is produced by fermentation cultures of Streptomyces antibioticus and has been used medicinally as its triacetyl ester troleandomycin against Gram-positive bacterial infections. The spiramycins (Figure 3.63) are macrolides produced by cultures of Streptomyces ambofaciens. The commercial antibiotic is a mixture containing principally spiramycin I, together with smaller amounts (10-15% each) of the acetyl ester spiramycin II and the propionyl ester spiramycin III. This antibiotic has recently been introduced into medicine for the treatment of toxoplasmosis, infections caused by the protozoan Toxoplasma gondii.

Tylosin (Figure 3.64) is an important veterinary antibiotic. It is produced by Streptomyces fradiae, and is used to control chronic respiratory diseases caused by Mycoplasma galliseptum in poultry, and to treat Gram-positive infections in pigs.

polyketide chain, which is also used to form oxygen heterocycles fused to the macrolide. Aver-mectin B1a exemplifies a typical structure and the basic carbon skeleton required to produce this can be postulated as in Figure 3.67. The starter unit in this case would be 2-methylbutyryl-CoA, which is derived from the amino acid L-isoleucine (compare necic acids, page 305, and tiglic acid, page 197).

Both malonyl-CoA and methylmalonyl-CoA are then utilized as extender units. The heterocyclic rings are easily accounted for: the spiro system is merely a ketal, though the tetrahydrofu-ran ring requires further hydroxylations of the basic skeleton for its construction. Avermectins are usually isolated as a mixture in which the main a component has a 2-methylpropyl group

CO2H C°2H

SCoA

Hemiketal Macrolide

O OH

avermectin B

SCoA

Stereochemistry Schiff Base

avermectin B

SCoA

L-Val

avermectin B[b

Figure 3.67

avermectin B[b

Figure 3.67

O OH

avermectin B2a avermectin B2a

ivermectin

ivermectin

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