Erythromycin origin

Interestingly, the selection of variants with reduced branching rates and enhanced strength of the cell wall results in a significantly enhanced production of erythromycin. This led Wardell et al. to search for the correlation between resistances to cell wall inhibitors bacitracin, tunicamycin and penicillin and production of the antibiotic. Significantly greater erythromycin titers were observed in the cultures of the tunicamycin- and penicillin-resistant mutants, whereas bacitracin-resistant mutant produced less antibiotic than the original strain. 

Bacterial resistance to erythromycin can originate by two possible mechanisms the inability of reaching the cell membrane, which is particularly relevant in the case of the microorganisms Enterobacteriaceae, or in the case of the presence of a methylated alanine in the 23 S ribosomal RNA of the 50 S subunit, which lowers the affinity of erythromycin to it. 

Clindamycin is indicated for the treatment of skin and soft-tissue infections caused by streptococci and staphylococci. It is often active against community-acquired strains of methicillin-resistant S aureus, an increasingly common cause of skin and soft tissue infections. Clindamycin is also indicated for treatment of anaerobic infection caused by bacteroides and other anaerobes that often participate in mixed infections. Clindamycin, sometimes in combination with an aminoglycoside or cephalosporin, is used to treat penetrating wounds of the abdomen and the gut infections originating in the female genital tract, eg, septic abortion and pelvic abscesses and aspiration pneumonia. Clindamycin is now recommended rather than erythromycin for prophylaxis of endocarditis in patients with valvular heart disease who are undergoing certain dental procedures. Clindamycin plus primaquine is an effective alternative to trimethoprim-sulfamethoxazole for moderate to moderately severe Pneumocystis jiroveci pneumonia in AIDS patients. It is also used in combination with pyrimethamine for AIDS-related toxoplasmosis of the brain. 

Like tetracyclines, macrolides are also polyketides that are isolated from bacteria and inhibit protein synthesis in certain bacteria. Erythromycin (A.32) is the original macrolide (Figure A.9). Clarithromycin (Biaxin, A.33) and azithromycin (Zithromax, A.34) are semisynthetic derivatives of erythromycin. 

Another aspect of erythromycin assembly that has been probed in vitro is the origin of the starter units [44], It has been suggested that the KS domain of module 1 of DEBS 1 + TE has the ability to prime its own biosynthesis by decarboxylation of methylmalonyl-CoA, generating starter-unit propionyl-CoA... 

KJ Weissman, M By croft, J Staunton, PF Leadlay. Origin of starter units for erythromycin biosynthesis. Biochemistry 37 11012-11017, 1998. 

Cethromycin (ABT-773) 39 (Advanced Life Sciences) had an NDA filed in October 2008 for the treatment of CAP.67 Advanced Life Sciences is also evaluating cethromycin 39 against other respiratory tract infections and in pre-clinical studies as a prophylactic treatment of anthrax post-exposure. Cethromycin 3968 70 is a semi-synthetic ketolide derivative of erythromycin 4071 originally synthesised by Abbott Laboratories,72 which like erythromycin 40, inhibits bacterial protein synthesis through binding to the peptidyl-transferase site of the bacterial 50S ribosomal subunit. Important macrolide antibiotics in clinical use today include erythromycin 40 itself, clarithromycin, azithromycin and, most recently, telithromycin (launched in 2001). 

Cholestatic hepatitis, which is associated primarily with erjdhromycin estolate, can be caused by all forms of erythromycin, including the base, estolate, ethylsuccinate, propionate, and stearate (39,41). Although it was originally speculated that a hypersensitivity reaction to the estolate ester rather than to the erjdhromycin itself was responsible for this adverse reaction (42), erythromycin does inhibit bile flow (43). Most probably the differences in hepatotoxicity between the various erythromycin derivatives are of a quantitative rather than a qualitative nature (44,45), perhaps because of better intestinal absorption of the estolate. Potentially severe but rare cholestatic liver injury occurs in perhaps up to 2-4% of... 

Topical erythromycin in benzoylperoxide, marketed for acne treatment, must be compounded by a pharmacist and requires subsequent refrigeration, warranting the development of alternative formulations. In a doubleblind, parallel-group, multicenter study in 327 patients, a single-use erythromycin in benzoylperoxide combination package was compared with the vehicle alone and the original, reconstituted formulation packaged in a jar. Dry skin was the most frequently reported skin-related adverse event it occurred in 3.2% of patients who used the preformulated erythromycin in benzoylperoxide and 5.0% of those who used the reconstituted erythromycin in benzoylperoxide (52). 

Erythromycin (XX) is labile at pH values below pH 4, and hence is unstable in the stomach contents. Erythromycin stearate (the salt of the tertiary aliphatic amine and stearic acid), being less soluble, is not as susceptible to degradation. The salt dissociates in the intestine to yield the free base, which is absorbed. There are differences in the absorption behaviour of the erythromycin salts and differences in toxicity, which may be related to their aqueous solubilities. Erythromycin ethylsuccinate was originally developed for paediatric use because its low water solubility and relative tastelessness were suited to paediatric formulations. The soluble lactobionate is used in intravenous infusions. 

Erythromycin and erythromycin estolate can be separated and quantitated by thin layer chromatography.Samples or standards should approximate 50 meg erythromycin estolate and 5-10 meg erythromycin base when spotted on silica gel G-25 plates. Approximately 120 ml of the developing solvent (methanol A.R.) is placed into the developing tank and allowed to equilibrate. The plate is developed until the solvent is approximately 15 cm from the origin The plate is removed and allowed to air dry. Antibiotic spots are visualized by spraying the plate with a fresh mixture of 95 ethanol/anis-aldehyde/conc. sulfuric acid, 90 5 5(v/v) followed by heating of the plate at 110 C for 10 minutes. The Rf values of erythromycin estolate and erythromycin base are approximately 0.7 and 0.35 respectively. 

Goto, H., Kawashima, Y, Kashimura, M., Morimoto, S., and Osawa, E. (1993). Origin of regi-oselectivity in the 0-methylation of erythromycin as elucidated with the aid of computational conformational space search. J. Chem. Soc. Perkin Trans. II1647-1654. 

Kataja, J., Huovinen, R, and Seppala, H. (2000). Erythromycin resistance genes in group A streptococci of different geographical origins. The macrolide resistance study group. J. Antimi-crob. Chemother. 46, 789-792. 

Since erythromycin and its derivatives exhibit several activities including motilin-like activity and anti-inflammatory actions, we expected them to be useful for treatment of systemic inflammatory diseases including chronic lower and upper airway diseases, chronic inflammatory bowel diseases, skin diseases of unknown origin, and autoimmune diseases. These inflammatory diseases are known to be associated with inflammatory cell activity. 

Erythromycin, a representative macrolide, and its derivatives have been found to show excellent anti-diffuse panbronchiolitis activity, and they now receive clinical attention beyond their original use as antibiotics. Moreover, the use of ivermectin, which was initially used as an antinematode agent for animals in 1981, procedures for exterminating onchocerciasis has been undertaken on a large scale. Consequently, in 1999 34 million people in an endemic area centered in Africa were saved from this disease with only a single annual administration. Thus, application of macrolides for clinical use has been a surprising development. 

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