SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF KETOLIDES (6-O-METHYL-3-OXOERYTHROMYCIN DERIVATIVES) - A NEW CLASS OF ANTIBACTERIALS HIGHLY POTENT AGAINST MACROLIDE-RESISTANT AND MACROLIDE-SUSCEPTIBLE RESPIRATORY PATHOGENS

In the search for new antibiotics active against macrolide-resistant p neumococci and Haemophilus influenzae, we synthesized a new class of 3 -oxo-6-O-methylerythromycin derivatives, so-called ''ketolides''. A ke to function was introduced in position 3 after removal of L-cladinose, a sugar which has long been thought essential. Further modifications of the macrolactone backbone allowed us to obtain three different seri es of 9-oxime, 11,12-carbamate, and 11,12-hydrazonocarbamate ketolides . These compounds were found to be very active against penicillin/eryt hromycin-resistant pneumococci and noninducers of MLSB resistance. The 11,12-substituted ketolide 61 (HMR 3004) demonstrated a potent activi ty against multiresistant pneumococci associated with a well-balanced activity against all bacteria involved in respiratory infections inclu ding H. influenzae, Mycoplasma catarrhalis, group A streptococci, and atypical bacteria. In addition HMR 3004 displayed high therapeutic act ivity in animals infected by all major strains, irrespective of their resistance phenotype.