Lecture: 6 MACROLIDES

Among the many antibiotics isolated from the actinomycetes is the group of chemically related compounds called the macrolides. In 1952, erythromycin and carbomycin were reported as new antibiotics, and they were followed in subsequent years by other macrolides. Currently, more than 40 such compounds are known, and new ones are likely to appear in the future. Of all of these, only two, erythromycin and oleandomycin, have been available consistently for medical use in the United States.

Chemistry

The macrolide antibiotics have three common chemical characteristics: (a) a large lactone ring (which prompted the name macrolide), (b) a ketone group, (c) a glycosidically linked amino sugar. Usually, the lactone ring has 12, 14, or 16 atoms in it, and it is often unsaturated, with an olefinic group conjugated with the ketone function.

They may have, in addition to the amino sugar, a neutral sugar that is linked glycosidically to the lactone ring (see discussion that follows under “Erythromycin”). Because of the dimethylamino group on the sugar moiety, the macrolides are bases that form salts with pKa values between 6.0 and 9.0. This feature has been used to make clinically useful salts. The free bases are only slightly soluble in water but dissolve in somewhat polar organic solvents. They are stable in aqueous solutions at or below room temperature but are inactivated by acids, bases, and heat.

Mechanism of Action and Resistance

Erythromycin binds selectively to a specific site on the 50S ribosomal subunit to prevent the translocation step of bacterial protein synthesis. It does not bind to mammalian ribosomes. Broadly based, nonspecific resistance to the antibacterial action of erythromycin among many species of Gram-negative bacilli appears to be largely related to the inability of the antibiotic to penetrate the cell walls of these organisms. In fact, the sensitivities of members of the Enterobacteriaceae family are pH dependent,with MICs decreasing as a function of increasing pH.

Furthermore, protoplasts from Gram-negative bacilli, which lack cell walls, are sensitive to erythromycin. A highly specific resistance mechanism to the macrolide antibiotics occurs in erythromycin-resistant strains of S. aureus. Such strains produce an enzyme that methylates a specific adenine residue at the erythromycin-binding site of the bacterial 50S ribosomal subunit. The methylated ribosomal RNA remains active in protein synthesis but no longer binds erythromycin. Bacterial resistance to the lincomycins apparently also occurs by this mechanism.

Spectrum of Activity

The spectrum of antibacterial activity of the more potent macrolides, such as erythromycin, resembles that of penicillin. They are frequently active against bacterial strains that are resistant to the penicillins. The macrolides are generally effective against most species of Gram-positive bacteria, both cocci and bacilli, and exhibit useful effectiveness against Gram-negative cocci.

Products Erythromycin

It achieved rapid early acceptance as a well- tolerated antibiotic of value for the treatment of various upper respiratory and soft-tissue infections caused by Gram-positive bacteria.

The commercial product is erythromycin A, which differs from its biosynthetic precursor, erythromycin B, in having a hydroxyl group at the 12-position of the aglycone. The amino sugar attached through a glycosidic link to C-5 is desosamine, a structure found in several other macrolide antibiotics.

As is common with other macrolide antibiotics, compounds closely related to erythromycin have been obtained from culture filtrates of S. erythraeus. Two such analogs have been found, erythromycins B and C. Erythromycin B differs from erythromycin A only at C-12, at which a hydrogen has replaced the hydroxyl group. The B analog is more acid stable but has only about 80% of the activity of erythromycin.

The C analog differs from erythromycin by the replacement of the methoxyl group on the cladinose moiety with a hydrogen atom. It appears to be as active as erythromycin but is present in very small amounts in fermentation liquors. Erythromycin is a very bitter, white or yellow-white, crystalline powder. It is soluble in alcohol and in the other common organic solvents but only slightly soluble in water.

The free base has a pKa of 8.8. Saturated aqueous solutions develop an alkaline pH in the range of 8.0 to It is extremely unstable at a pH of 4 or below. The optimum pH for stability of erythromycin is at or near neutrality. Erythromycin may be used as the free base in oral dosage forms and for topical administration. To overcome its bitterness and irregular oral absorption (resulting from acid destruction and adsorption onto food), various entericcoated and delayed-release dose forms of erythromycin base have been developed.

Erythromycin has been chemically modified with primarily two different goals in mind:

(a) to increase either its water or its lipid solubility for parenteral dosage forms. (b) to increase its acid stability (and possibly its lipid solubility) for improved oral absorption. Modified derivatives of the antibiotic are of two types: acid salts of the dimethylamino group of the desosamine moiety (e.g., the glucoheptonate, the lactobionate, and the stearate) and esters of the 2 — - hydroxyl group of the desosamine (e.g., the ethylsuccinate and the propionate, available as the lauryl sulfate salt and known as the estolate).

The stearate salt and the ethylsuccinate and propionate esters are used in oral dose forms intended to improve absorption of the antibiotic. The stearate releases erythromycin base in the intestinal tract, which is then absorbed. The ethylsuccinate and the estolate are absorbed largely intact and are hydrolyzed partially by plasma and tissue esterases to give free erythromycin.