Propionyl erythromycin

Synonyms. Erythromycin Propionate Lauryl Sulphate Propionyl Erythromycin Lauryl Sulphate. 

Synonyms for this compound include erythromycin propionate lauryl sulfate erythromycin propionate dodecyl sulfate lauryl sulfate salt of the propionic ester of erythromycin monopropionylerythromycin lauryl sulfate and propionyl erythromycin lauryl sulfate. 

The maximum ultraviolet absorption of aqueous solutions of monopropiony1 erythromycin is at 285 nm. Monopropionyl erythromycin was used because propionyl erythromycin lauryl sulfate is practically insoluble. Murphy4 has reported that the ultraviolet spectrum of the esters of erythromycin are not significantly... 

When mounted in mineral oil ana examined by means of a polarizing microscope, propionyl erythromycin lauryl sulfate exhibits birefringence and extinction positions when the microscope stage is revolved. ... 

Erythromycin estolate differs from other forms of erythromycin in that it is extremely stable to acid hydrolysis.5 Erythromycin liberated from the ester by mild alkaline hydrolysis is subject to rapid decomposition in strongly acid solutions. Kavanagh has stated that deterioration of erythromycin increases with an increase in temperature and decreases with an increase in pH up to 8.0. Buffered aqueous solutions of erythromycin base are quite stable at this pH. Acetone solutions of the ester form are stable, while acetone solutions of the propionyl erythromycin lauryl sulfate preparation are not. Powders and dry formulations are stable for at least five years. Liquid preparations become unacceptable after 2 years due to undesirable taste. 

Ester derivatives of erythromycin, shown in Table 4, were synthesized soon after its discovery (124—126). They are readily prepared by acylation of the 2-hydroxyl group the neighboring 3r-dimethylamino group directs acylation to this site. Commonly used esters of erythromycin are propionate, acetate, ethyl succinate, and ethyl carbonate (30). 2r-Esters do not bind bacterial ribosomes, however, and consequently must be hydrolyzed back to the parent to exert antibacterial activity (127). Ester derivatives are still being prepared (128,129). 2,-0-Acetylerythromycin stearate, also known as erythromycin acistrate, is an example undergoing clinical trial (11,130,131). Two salts of 2,-0-propionyl-erythromycin, N-acetylcysteinate (erythromycin stinoprate) and mercaptosuccinate, were prepared to combine antibiotic and mucolytic properties in a single agent (132—134). 

Other types of reactions with possible allergic causes are uncommon (Bennett 1965 Beaty and Petersdorf 1966). In a long-term study of 20,525 patients treated with propionyl erythromycin and erythromycin estolate, the incidence of skin eruptions was found to be 0.5% (Kuder 1960). A total of 548 allergic children, most of them atopic, were treated with erythromycin ethylsuccinate and again... 

Kucers A, Bennet NMcK (1975) The use of antibiotics, 2nd edn. Heinemann, London Kuder HV (1960) Propionyl erythromycin. A review of 20,525 case reports for side effect data. Clin Pharmacol Ther 1 604-609... 

In the presence of its natural substrates, propionyl-CoA, methylmalonyl-CoA, and NADPH, DEBS 1-TE was initially shown to catalyze the formation of lactone in a cell-free system [36]. Concomitant work on a similar bimodular system called DEBS 1+TE (Fig. 9c) [37] in a cell-free extract and with partially purified protein, demonstrated that it too was competent for biosynthesis of the triketide lactone [33], These experiments set the stage for more rigorous investigation of mechanistic aspects of erythromycin biosynthesis. 

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... 

S Donadio, MJ Staver, L Katz. Erythromycin production in Saccharopolyspora erythraea does not require a functional propionyl-CoA carboxylase. Mol Microbiol 19 977-984, 1996. 

Cholestatic jaundice This side effect occurs, especially with the estolate form of erythromycin, presumably as the result of a hypersensitivity reaction to the estolate form (the lauryl salt of the propionyl ester of erythromycin). It has also been reported for other forms of the drug. 

The molecular backbone of the antibiotic erythromycin A [6-desoxy-erythronolide B (3)] is built up repetitively from one propionyl-coenzyme A (1) and six methyl-malonyl-coenzyme A (2) constituents by the action of polyketide-synthase, which itself consists of three proteins (DEBS 1 -3) (Schemes 1 and 2). Each protein contains two modules with several separate, cat-alytically active domains. In the first section, DEBS 1 carries an additional loading zone, and DEBS 3 contains a thioesterase in the final segment, catalyzing the decoupling of the product by building the lactone ring [6],... 

The biosynthesis of erythromycin can be divided into two phases (Scheme 1). In the first constructive phase of the pathway a set of key enzymes, collectively known as the polyketide synthase (PKS), assembles the typical polyketide chain by sequential condensation of one unit of propionyl-CoA and six units of methylmalonyl-CoA 6. The initially formed chain is cyclised to give the first macrocychc lactone (macrolide) intermediate 6-deoxyerythronolide B 7 [6,7]. In the second phase 6-deoxyerythronohde B is elaborated by a series of tailoring enzymes which carry out regiospecific hydroxylations, glycosylations and a methylation (of an added sugar residue) to give finally erythromycin A. The core polyketide structure is generated by the PKS in phase one, but the later steps of phase two are essential to produce active antibiotics. 

Most of the data on rokitamycin have been published in Japanese and Italian journals. As a propionyl ester of leucomycin, rokitamycin has an antimicrobial spectrum similar to that of erythromycin, it is especially potent against L. pneumophila, M. pneumoniae, and Chlamydia. Like other 16-membered macrolides, it is active against bacteria that are inducibly resistant to erythromycin but inactive against strains that are constitutively resistant to macrolide-lincosamide-streptogramin B antibiotics. 

This putative new concept can account for the reason why rokitamycin acts as a bactericidal agent against susceptible cells despite the fact that " C-labeled rokitamycin Ki = 3.4 X 10" M), a 3"-0-propionyl derivative of leucomycin Aj, has about half as much affinity for the ribosome as erythromycin = 1.6 x 10" M) does. In fact, " C-labeled rokitamycin is hardly replaced by nonlabeled rokitamycin, when the labeled drug had previously been bound to ribosomes from susceptible S. aureus [34, 51]. 

Stubbs, C. Kanfer, I. High-performance liquid chromatography of erythromycin propionyl ester and erythromycin base in biological fluids. J.Chromatogr., 1988, 427, 93-101 [extracted erythromycin, erythromycin propionate oleandomycin (IS) electrochemical detection column temp 35 serum urine SPE pharmacokinetics LOQ 250 ng/mL]... 

Cladinose analogues of 16-membered macrolide antibiotics have been prepared. Ethyl P-L-cladinoside was produced by ethanolysis of erythromycin A, and, after alkylation at 0-4, the alkylated products were linked to 0-4 of the mycaminose residue to give 3"-O-methyl-4"-0-alkyl derivatives of 9-dehydro-3-0-propionyl-leucomycin V. Microbial glycosylation by a strain of Streptomyces hygroscopicus has been used to make the 2 -0-P-D-glucopyranosyl derivatives of erythromycin B, erythromycin A oxime and azithromycin. ... 

---