Abstract

Our studies on the resistance mechanisms and chemical modifications of aminoglycoside antibiotics led to the synthesis of arbekacin (ABK), which was refractory to most aminoglycoside-modifying enzymes in resistant bacteria. In 1990, ABK was launched into clinical uses in Japan as a chemotherapeutic agent for the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). By 1993 only a few MRSA strains moderately resistant to ABK (MIC, 6.25-12.5 micrograms/ml) had clinically been isolated. ABK was modified by the reaction with an excess of an enzyme preparation extracted from an ABK-resistant strain (12.5 micrograms/ml) and three inactivated products were produced, consisting mainly of ABK 2''-phosphate along with small amounts of 6'-N-acetyl-ABK and the doubly modified ABK. Based on these results, replacement of the 2''-hydroxyl by amino group in dibekacin (DKB) or in ABK was designed to obtain potent active derivatives against MRSA. Conversion of the 2''-hydroxyl group by DMSO-DCC oxidation followed by reductive amination with NH4OAc-NaBH3CN gave 2''-amino-2''-deoxy-DKB (D1) and -ABK (A1). Their 5-deoxy (D2 and A2), 5-epifluoro (D3 and A3) and 5-epiamino (D4 and A4) derivatives were also synthesized. All 2''-amino-2''-deoxy-ABK derivatives (A1, A2, A3 and A4) showed excellent activities against MRSA and Gram-negative bacteria, as expected. Among them, A4 having low acute toxicity and nephrotoxicity was selected as a new candidate for anti-MRSA agent.