14-Membered macrolides erythromycin

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. 

Telithromycin (16 Ketek ) Erythromycin A 14-Membered macrolide Semi-synthetic NP Microbial Antibacterial Blocks bacterial polypeptide chain growth 181, 182, 183, 226-230... 

Semisynthetic Derivatives. Erythromycin has been the principal subject of modification of 14-membered macrolides some of the derivatives are being commercially launched. Derivatives of erythromycin and oleandomycin include 2-U-nee ly I erythromycin (C331129NO t. 2 -O-propionylerythromycin (QoHtiNOm), erythromycin ethyl carbonate (C/0H71NO15), erytliromydn ethyl succinate (C 3H75NOi2), tn-O-acetyloleandomycin (C4iHc7NOi5), erythromycin-11,12-carbonate... 

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],... 

Although spiramycin is used to treat toxoplasmosis, more potent inhibitors of Toxoplasma gondii have been reported [183-185]. In contrast to derivatives of erythromycin, activity was not observed from several 16-membered macrolides against Mycobacterium avium complex [186]. Similar trends have been noted with several other bacterial and parasitic pathogens in which 16-membered macrolides have not matched the promising activity shown by erythromycin derivatives [177]. 

A review of 16-membered macrolide antibiotics (Chapter 5) complements a survey of semi-synthetic erythromycins which appeared in Volume 30. Further work in this direction is expected to yield new antibiotics of greater efficiency and a lower level of side-effects. The antibacterial effects of silver have been known for a long time and are assessed in Chapter 7. 

The basic structure of the macrohde antibiotics is characterized by a lactonic cycle with two osidic chains, and they are classified according to the number of carbon atoms in the cycle 14-membered macrohdes (for example clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin), 15-membered macrolides (for example azithromycin), and 16-membered macrolides (for example josamycin, midecamycin, spiramycin). 

Semisynthetic Derivatives. Erythromycin has been the principal subject of modification of 14-membered macrolides some of the derivatives are being commercially launched (116). 

Other macrolides have been prepared which represent hybrids of structures within the 14-membered family, within the 16-membered family, or between the two families. These hybrids have been made by chemical, bioconversion, or genetic manipulations. The 9-0-[(2-methoxyethoxy)methyl]oxime of tylosin (Table 7) was synthesized, using the oxime found in roxithromycin (33) (369). 3-O-Qadinosyl derivatives of 16-membered macrolides were synthesized in which the neutral sugar of erythromycin (Table 3) was attached to tylosin derivatives at their 3-hydroxyl group, analogous to its position in erythromycin... 

Macrolides inhibit growth of bacteria by inhibiting protein synthesis on ribosomes (17,415,416). Bacterial resistance to macrolides is often accompanied by cross-resistance to lincosamide and streptogramin B antibiotics (MLS-resistance), which can be either inducible or constitutive (417). 14-Membered macrolides generally induce resistance to themselves, whereas 16-membered macrolides do not consequendy, one advantage of the latter is their activity against bacteria which are inducibly resistant to erythromycin. Both 14- and 16-membered macrolides lack activity against constitutively resistant strains (387,388). 

Kinoshita, K., Williard, P.G., Khosla, G. Gane, D.E. Precursor-directed biosynthesis of 16-membered macrolides by the erythromycin polyketide synthase. J. Am. Chem. Soc. 123, 2495-2502 (2001). 

This chapter deals with recent progress in the chemical modification and structure-activity relationships of 14- and 15-membered macrolides (mainly erythromycin derivatives), 16-membered macrolides (mainly the leucomycin and tylosin families), and the avermectin family of macrolides, showing nematocidal, insecticidal, and arachnidicidal activities. Previous reviews of these macrolides were given by Sakakibara and Omura in the first edition of this book in 1984 [1]. 

Adachi, T. (1989). 15-Membered macrolides via translactonization in 14-hydroxy-6-0-methyl-erythromycin A. J. Org. Chem. 54, 3507-3510. 

Tylosin [46-49] (Fig. 6), produced by Streptomyces fradiae, was one of the first antibiotics for which a comprehensive set of blocked mutants was isolated. They were used to help define the biosynthetic pathway. Whereas erythromycin is a 14-membered macrolide, tylosin has a 16-membered lactone structure. The gene for the final step of biosynthesis was cloned by reverse genetics from the protein sequence of the enzyme [46], and specific segments of surrounding DNA were found to complement other classes of blocked mutants. The formation of tylosin aglycon, protylonolide, is involved in five polyketide synthases. 

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,... 

Dirithromycin is a 14-membered macrolide antibiotic approved for clinical use in the United States. Its in vitro activities are two- to fourfold less than those of erythromycin against gram-positive bacteria and a variety of clinical isolates, but it is fourfold more active than erythromycin against Bordetella pertussis [1,8,... 

---