Synthesis and antimicrobial evaluation of dirithromycin (AS-E 136; LY237216), a new macrolide antibiotic derived from erythromycin.

Dirithromycin is a 9-N-11-O-oxazine derivative which is formed by condensation of 9(S)-erythromycylamine with 2-(2-methoxyethoxy)acetaldehyde. Dirithromycin is hydrolyzed, either under acidic conditions or in vivo, to its major active metabolite, 9(S)-erythromycylamine. The antimicrobial spectrum of dirithromycin is similar to that of erythromycin; both antibiotics are active against gram-positive bacteria, Legionella spp., Helicobacter pylori, and Chlamydia trachomatis. Comparable results were obtained for each antibiotic in MIC and MBC determinations and in the potential development of resistance in vitro. The effects of human serum, bacterial growth media, test methodology, and inoculum size on MICs were similar for each antibiotic. In standard mouse protection studies, dirithromycin was more efficacious than erythromycin against experimental infections after subcutaneous administration of antibiotic. These results were consistent with pharmacokinetic studies in rodents, which showed that dirithromycin gave more persistent concentrations of antibiotic in serum and tissues than were achieved with erythromycin. These studies indicate that dirithromycin possesses antimicrobial activity comparable to that of erythromycin in vitro but is more active than erythromycin in vivo, which may be attributable to the persistence of antimicrobial activity in the tissue(s) of the test animals.

Structure-activity studies of 20-deoxo-20-amino derivatives of tylosin-related macrolides.

Reductive amination of the C-20 aldehyde group of tylosin and related macrolides yielded a large series of derivatives with potentially useful antibiotic properties. Evaluation of these new compounds was conducted on the basis of: 1) Broad antimicrobial spectrum in vitro, with particular emphasis on inhibition of Pasteurella multocida and Pasteurella haemolytica; 2) in vivo efficacy, especially when given orally, against P. multocida in experimental infections in chicks; and 3) bioavailability after oral administration to laboratory animals. The most useful activity was found within a series of derivatives produced by reductive amination of desmycosin with secondary amines.

Antimicrobial prophylaxis of experimental endocarditis caused by Staphylococcus epidermidis.

Using two different strains of Staphylococcus epidermidis in a rat model of experimental endocarditis, we examined the prophylactic efficacy of cefamandole (200 mg/kg/dose), cefazolin (200 mg/kg/dose), nafcillin (200 mg/kg/dose), and vancomycin (20 mg/kg/dose). In vitro susceptibility testing demonstrated that both test strains were resistant to methicillin and cefazolin and susceptible to cefamandole and vancomycin. A 10(6) cfu inoculum was used for both strains, an inoculum which produced endocardial infections in greater than 90% of rats. Initial doses of each antibiotic were given 45 min to 1 h prior to bacterial challenge and were followed by six additional doses of each antibiotic administered subcutaneously every 6 h. The efficacy rates of cefamandole (84.0%) and cefazolin (70.8%) were exactly the same for rats infected with either S. epidermidis strain. Similar efficacy rates were seen in rats infected with either strain and treated with vancomycin (94.4% and 86.7%). Unlike the other three drugs, the efficacy of nafcillin was quite different in rats challenged with the two strains (62.5% and 38.5%, p = 0.19). It appears that cefamandole and cefazolin may have considerable prophylactic efficacy against certain infecting strains of methicillin-resistant, coagulase-negative staphylococci when relatively large doses of cephalosporins are administered subcutaneously in this animal model.

Synthesis and antibacterial evaluation of N-alkyl vancomycins.

Over eighty N-alkyl vancomycins were synthesized by reductive alkylation of vancomycin with the appropriate aldehydes. The N-alkyl vancomycins exhibit greater antibacterial activity than the corresponding N-acyl vancomycins and the parent antibiotic. Some of these semisynthetic vancomycins are five times more active than vancomycin. The N-alkyl vancomycins also show longer elimination half-lives in rats than vancomycin.

Synthesis and evaluation of tylosin-related macrolides modified at the aldehyde function: a new series of orally effective antibiotics.

Modification of the aldehyde group in tylosin and related macrolide antibiotics dramatically enhanced the oral efficacy of the derivatives against experimental infections caused by susceptible bacteria in laboratory animals. A large number and wide variety of aldehyde-modified macrolide derivatives were prepared, utilizing the Mitsunobu reaction and other chemical transformations. Evaluation of in vitro and in vivo antimicrobial activity indicated that derivatives of demycarosyltylosin (desmycosin) combined the broadest spectrum of antimicrobial activity with the best efficacy and bioavailability after oral administration.

In vitro and in vivo evaluation of C-20- and C-23-modified derivatives of tylosin against veterinary pathogens.

Three series of semi-synthetic derivatives of tylosin-related macrolides were evaluated for utility in veterinary medicine. 23-Modified derivatives of 5-O-mycaminosyltylonolide (OMT) possessed potent activity in vitro against species of Pasteurella and Mycoplasma. An experimental infection in chicks caused by Pasteurella multocida was utilized to evaluate efficacy; several of these derivatives of OMT effectively treated the infection when given subcutaneously, but none were effective after oral administration in drinking water. Macrolides retaining the 4'-O-mycarosyl moiety (tylosin, DMT) had relatively poor activity against Pasteurella in vitro. Certain 20-modified derivatives of desmycosin demonstrated good oral bioavailability in chicks and a lead compound with oral efficacy in the Pasteurella infection model was discovered.

Synthesis, antimicrobial evaluation and structure-activity relationships within 23-modified derivatives of 5-O-mycaminosyltylonolide.

A large series of C-23-modified derivatives of 5-O-mycaminosyltylonolide were synthesized, in which the C-23 hydroxyl group was replaced by halo, aryl ether or thioether, azido, amino or dialkylamino substituents via SN2 displacement reactions. The majority of derivatives possessed excellent in vitro activity against a variety of aerobic and anaerobic bacteria. While some of the compounds treated experimental infections in rodents by parenteral administration, none showed any significant efficacy or bioavailability after oral dosing. Novel rearrangement products were obtained from some of the reactions; these were identified as 13,23-cyclopropyl-12,22-exomethylene and 13,23-cyclopropyl-12-alkoxy derivatives.

Synthesis and antimicrobial evaluation of acyl derivatives of 16-membered macrolide antibiotics related to tylosin.

A large number and wide variety of acyl derivatives of the tylosin-related macrolides 23-demycinosyltylosin (DMT), 23-demycinosyloxytylosin (DMOT) and 5-O-mycaminosyltylonolide (OMT) were synthesized and evaluated. This encompassed conversion of the hydroxyl groups at 2',4' and 23 of the appropriate macrolides to the corresponding esters, in which a variety of different substitution patterns were examined. A wide range of acyl substituents was investigated, particularly for 23-O-acyl derivatives of OMT, since these were substantially more active in vitro than OMT itself. However, the acyl derivatives which were prepared demonstrated no substantial improvement in oral efficacy or bioavailability over the parent macrolides.