Macrolide antibiotics antibacterial activity

Sakakibara, H., Okekawa, O., Fujiwara, T., Aizawa, M., and Omura, S. (1981). Acyl derivatives of 16-membered macrolides. n. Antibacterial activities and serum levels of 3"-0-acyl devira-tives of leucomycin. J. Antibiot. 34, 1011-1018. 

Amphotericin-B, an amphoteric polyene macrolide remains the most effective for severe systemic mycoses. It is indicated for systemic mycoses such as disseminated candidiasis, cryptococcosis, aspergillosis, mucormycosis, coccidioidomycosis, histoplasmosis, extracutaneous sporotrichosis and blastomycosis. It is a fungicidal antibiotic without antibacterial activity. It binds to ergosterol in the... 

Theriault RJ, Karwowski JP, Jackson M, Girolami RL, Sunga GN, Vojtko CM, Coen LJ (1987) Tiacumicins, A Novel Complex of 18-Membered Macrolide Antibiotics I. Taxonomy, Fermentation and Antibacterial Activity. J Antibiot 40 567... 

An interesting exception to the absolute validity of the tifth postulate is the considerable activity of chloramphenicol derivatives in cell-free model systems of protein synthesis when these derivatives are substituted with amino acyl residues instead of with dichloroacetyl as is the antibiotic itself (rev. in 2°)). This has been traced to the necessity of the dichloroacetyl grouping in aiding in the permeation of the antibiotic through the bacterial envelope 21 The amino acyl derivatives have very low antibacterial activity 20. Permeation failures of actinomycin D, macrolides and distamycin A with respect to certain families of bacteria occlude the action of these antibiotics on their intracellular drug receptors and target reactions but can be overcome experimentally by measures which render test organisms permeable. 

The enantiotopic discrimination of hydrogens during oxidation of unactivated C—H bonds by microorganisms is synthetically extremely useful, and some examples are shown in Scheme The resultant products are valuable chiral synthons. For example (/ )-3-hydroxybutanoic acid (7) a versatile homochiral synthon, can be used in the synthesis of antibacterials. > (5)-2-Methyl-3-hydn>xypropanoic acid (8) has been widely employed as a source of chirality, for example in the synthesis of maysine, macrolide antibiotics and both (/ )- and (S)-muscone. A variety of other optically active 3-hydroxy aliphatic carboxylic acids can be prepared by analogous methods. 

Extensive early studies of in vitro and in vivo structure-activity relationships within the leucomycin family revealed correlations between the number and type of O-acyl substituents and the compounds antibacterial potency, efficacy in treating experimental infections, and serum antibiotic concentrations [26]. Consequently, esterification of all hydroxyl groups within several leucomycin-related macrolides was conducted to find derivatives with better antibiotic activity and pharmaceutical properties (such as greater water solubility and masking their extremely bitter taste). From such investigations with midecamycin, miokamycin was synthesized and characterized as a useful new macrolide antibiotic [24, 27]. It has now been commercially launched in several countries [5]. 

The in vitro antibacterial activity of members of leucomycin complex increased with increasing partition coefficient and removal of testification of the three hydroxyl of the macrolide ring. The in vitro activity of the NH lincomycin was positively correlated with log partition coefficeint (Optimum > 2.7). Electronic and steric factors also influenced the activity of leucomycin and lincomycin antibiotics (78). 

Tilmicosin, Figure 1, is a new semisynthetic antibiotic derived from the macrolide antibiotic tylosin. The synthesis and antibacterial activity of tilmicosin have been described by Debono, et al. and Kirst, et al. (/-4). Tilmicosin has in vitro activity against a variety of Gram positive and Gram negative bacteria, as well as mycoplasma species. It is effective for treatment of bovine respiratory disease caused by Pasteurella haemolytica when administered as a single subcutaneous injection (5, 6). This paper describes the excretion, tissue residue pattern, and metabolism of tilmicosin when injected into cattle, and also gives comparative metabolism data from rats which were dosed orally. 

The macrolide lactone antibiotics are isolated primarily from the genus Streptomyces. Their antibacterial activity is mostly in the Gm+ spectrum. They are classified on the basis of the size of the macrocyclic lactone rings, the aglycone component of the compound. These are 12-, 14-, or 16-membered rings, glycosidically linked to one or more amino sugars, thus making these polyfunctional compounds basic (Fig. 6-25). 

Both in vitro and in vivo activity is reduced by an increase in the acyl group length in the 2 -0-acyl derivatives. The MIC values of the 2 -0-acetyl and 2 -0-propionyl derivatives are nearly the same as that of the parent antibiotic. Because the 2 -0-acyl is easily hydrolyzed in aqueous solution, the potent antibacterial activity has been explained by the hydrolysis of 2 -0-acyl group during bioassays. For this reason, the 2 -hydroxyl group has been considered to be one of the functional groups essential for the biological activity of the macrolide. 

Macrolide antibiotics are a homogeneous group of antimicrobial drugs that have been used to treat clinical infections for several decades. The most clinically useful classification of the macrolides is based on the size of the lactone ring that forms the chemical nucleus of each macrolide molecule [1, 2]. The 14- and 15-membered macrolides include erythromycin, clarithromycin, dirithromycin, roxithromycin, and azithromycin. Erythromycin is the oldest and still the most important of the macrolide antibiotics because it is a useful alternative to penicillin G. It is one of the safest antibiotics available. Clarithromycin and azithromycin have shown some advantages over erythromycin in their antibacterial activity,... 

These studies on modifications to erythromycin A have provided a great deal of important and interesting pharmacokinetic improvements, broadening an antibacterial spectrum and developing potency. For details, see Weisblum [183] and Bryskier et al. [207, 208]. Further work on structure-activity relationships in macrolide antibiotics with due consideration for their water solubility will provide a sufficient opportunity to improve antibacterial macrolides. 

Carbomycin, Magnamycin. Sixteen -membered -ring macrolide antibiotic complex similar to leucomycin, q.v and erythromycin, q.v., produced by Streptomyces halstedil lsoln and antibacterial activity F. W. Tanner et al, Anti-... 

Erythromycin Lactobionate. 4-O-0-D-Gatacio-pyranosyt-o-glaconic acid compd with erythromycin (1 1) Erythrocin Lactobionate. Semi-synthetic macrolide antibiotic prepd from erythromycin beae and lactobiono-6-lactone in water-acetone Hoffhine, U.S. pat. 2,761,859 (1956 to Abbott) alternate prepn and antibacterial activity S. K. Dutta. K. S. Basu, U.S. pat. 4,137,397 (1979 to Jadavpur Univ.). Pharmacokinetics R. L. Parsons et al. J. Inc Med. Res. 8, suppl. 2, 15 (1980). 

The macrolide antibiotics are a group of compounds which have as a nucleus a ma-crocyclic lactone ring to which one or more sugars are attached. These sugars are essential for the antibiotic activity. Only three of the macrolides, i.e., erythromycin, oleandomycin, and spiramycin are used in human clinical practice, while a fourth, tylosin, is used in veterinary medicine and as a food preservative in industrial canning. These are all weakly alkaline and only slightly soluble in water. Erythromycin is the most active antibiotic of this group (Fig. 7). All of them are able to inhibit bacterial protein synthesis and are characterized by their bacteriostatic qualities. The antibacterial spectrum is similar to that of benzylpenicillin. 

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