NEW 2"-AMINO DERIVATIVES OF ARBEKACIN, POTENT AMINOGLYCOSIDE ANTIBIOTICS AGAINST METHICILLIN-RESISTANT Staphylococcus aureus

At the end of 1990, arbekacin (ABK, 1-N-[(S)-4-amino-2-hydroxybutyryl] 3',4'-dideoxykanamycin B) was launched into Japan as a useful chemotherapeutic agent for the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). By 1992 only a few MRSA strains which were moderately resistant to ABK (MIC, 12.5 similar to 25 mu g/ml) were clinically isolated. In a previous paper, we reported that ABK was modified by reaction with excess of a crude enzyme preparation extracted from ABK-resistant MRSA (25 mu g/ml) and ABK 2"-O-phosphate was afforded as a major inactivated product along with two minor products, 6'-N-acetyl-ABK and the double modified ABK. Based on these results, replacement of the 2"-hydroxyl group by amino group in ABK or in dibekacin (DKB, 3',4'-dideoxykanamycin B) was designed to obtain potent derivatives against MRSA. Among known aminoglycoside antibiotics, only seldomycin factor 5 isolated from the culture of Streptomyces hofunensis contains a 2,3-diamino sugar in the structure. MCALPINE and colleagues described that 3'-deoxyseldomycin factor 5 showed a good antibacterial activity. In this communication, we report the synthesis and antibacterial activity of 2"-amino-2"-deoxy-ABK, 2"-amino-5,2"-dideoxy-ABK (2), 2"-amino-2"-deoxy-DKB and 2"-amino-5,2"-dideoxy-DKB.