Among the many antibiotics isolated from the actinomycetes is the group of chemically related compounds called the macrolides. In 1950, picromycin, the first of this group to be identified as a macrolide compound, was first reported. 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. In recent years, interest has shifted away from novel macrolides isolated from soil samples (e.g., spiramycin, josamycin, and rosamicin), all of which thus far have proved to be clinically inferior to erythromycin and semisynthetic derivatives of erythromycin (e.g., clarithromycin and azithromycin), which have superior pharmacokinetic properties because of their enhanced acid stability and improved distribution properties.
The macrolide antibiotics have three common chemical characteristics: (a) a large lactone ring (which prompted the name macrolide), (b) a ketone group, and (c) a glycosidi-cally 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. (The polyene macrocyclic lactones, such as natamycin and amphotericin B; the ansamycins, such as rifampin; and the polypeptide lactones generally are not included among the macrolide antibiotics.) They may have, in addition to the amino sugar, a neutral sugar that is linked glycosidi-cally 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. The chemistry of macrolide antibiotics has been the subject of several reviews.190,191
Some details of the mechanism of antibacterial action of erythromycin are known. It binds selectively to a specific site on the 50S ribosomal subunit to prevent the translocation step of bacterial protein synthesis.192 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.193 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.194,195 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.
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, especially Neisseria spp. Many of the macrolides are also effective against Treponema pallidum. In contrast to penicillin, macrolides are also effective against Mycoplasma, Chlamydia, Campylobacter, and Legionella spp. Their activity against most species of Gram-negative bacilli is generally low and often unpredictable, though some strains of H. influenzae and Brucella spp. are sensitive.
Early in 1952, McGuire et al.196 reported the isolation of erythromycin (E-Mycin, Erythrocin, Ilotycin) from Streptomyces erythraeus. 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. It is also effective against many venereal diseases, including gonorrhea and syphilis, and provides a useful alternative for the treatment of many infections in patients allergic to penicillins. More recently, erythromycin was shown to be effective therapy for Eaton agent pneumonia (Mycoplasma pneumoniae), venereal diseases caused by Chlamydia, bacterial enteritis caused by Campylobacter jejuni, and Legionnaires disease.
Was this article helpful?
Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...