ANTIMICROBIAL CHARACTERIZATION AND INTERRELATIONSHIPS OF DIRITHROMYCIN AND EPIDIRITHROMYCIN

Dirithromycin is the 9-N,11-O-oxazine adduct formed from 9(S)-erythrom ycylamine and 2-(2-methoxyethoxy)acetaldehyde in which the methoxyetho xymethyl substituent on the oxazine ring possesses the R configuration . Epidirithromycin is its isomer in which the methoxyethoxymethyl subs tituent has the opposite (S) configuration. Both compounds readily epi merize in solution, reaching an equilibrium ratio of 85:15 in favor of dirithromycin, given sufficient time. The rate of interconversion is dependent upon pH, temperature, and solvent, An enriched sample of epi dirithromycin (95% purity) was synthesized by condensing erythromycyla mine and 2-(2-methoxyethoxy)acetaldehyde in diethyl ether as the react ion solvent, and the product was fully characterized by nuclear magnet ic resonance spectroscopy and high-pressure liquid chromatographic (HP LC) analysis. Both oxazine derivatives readily hydrolyze to erythromyc ylamine, so ail three compounds exhibit the same antibiotic activity i n vitro. In order to determine whether dirithromycin itself possesses significant antimicrobial activity without initial hydrolysis to eryth romycylamine, inhibition of cell-free ribosomal protein synthesis was measured under conditions which were adapted to minimize hydrolysis, a s measured by ana lytical HPLC in parallel experiments. Under these pa rticular conditions, inhibition of ribosomal protein synthesis by diri thromycin was <10% of the value measured for erythromycylamine.