Studies on macrolide antibiotics I. Synthesis and antibacterial activity of erythromycin A 9-O-substituted oxime ether derivatives against Mycobacterium avium complex

A series of erythromycin A 9-O-substituted oxime ether derivatives have bee n synthesized and evaluated for antibacterial activity against Mycobacteriu m avium complex (MAC) and Staphylococcus aureus. These compounds possessed stronger in vitro activity against MAC including macrolide-resistant strain s than clarithromycin (2), although in vitro antibacterial activities of th ese compounds were less than that of 2 against Staphylococcus aureus. Our s tudies found that several factors contribute to the antibacterial activity against MAC. The length and spatial orientation of the substituent at 9-pos ition were found to significantly influenced the anti-MAC activity, especia lly against macrolide-resistant strains. Of all the compounds prepared, ery thromycin A 9-[O-(4-phenylbutyl)oxime] (12q) and erythromycin A 9-[O-(3-phe noxypropyl)oxime] (12t) possessed 16 times stronger antibacterial activity than 2 against clarithromycin-resistant strains. Surprisingly, the minimum inhibitory concentrations (MICs) of 12q and 12t against the resistant strai ns were almost same as those against the susceptible strains. These results suggest that the erythromycin A 9-O-substituted oxime ether derivatives wo uld be promising macrolide antibiotics.