Novel aprosamine derivatives were synthesized for the development of aminoglycoside antibiotics active against multidrug-resistant Gram-negative bacteria. The synthesis of aprosamine derivatives involved glycosylation at the C-8' position and subsequent modification (epimerization and deoxygenation at the C-5 position and 1-N-acylation) of the 2-deoxystreptamine moiety. All 8'-β-glycosylated aprosamine derivatives (3a-h) showed excellent antibacterial activity against carbapenem-resistant Enterobacteriaceae and 16S ribosomal RNA methyltransferase-producing multidrug-resistant Gram-negative bacteria compared to the clinical drug, arbekacin. The antibacterial activity of 5-epi (6a-d) and 5-deoxy derivatives (8a,b and 8h) of β-glycosylated aprosamine was further enhanced. On the other hand, the derivatives (10a,b and 10h) in which the amino group at the C-1 position was acylated with (S)-4-amino-2-hydroxybutyric acid showed excellent activity (MICs 0.25-0.5 μg/mL) against resistant bacteria that produce the aminoglycoside-modifying enzyme, aminoglycoside 3-N-acetyltransferase IV, which induces high resistance against parent apramycin (MIC > 64 μg/mL). In particular, 8b and 8h showed approximately 2- to 8-fold antibacterial activity against carbapenem-resistant Enterobacteriaceae and 8- to 16-fold antibacterial activity against resistant Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, compared to apramycin. Our results showed that aprosamine derivatives have immense potential in the development of therapeutic agents for multidrug-resistant bacteria.
Keywords: Gram-negative bacteria; aminoglycoside; antibiotic; aprosamine; carbapenem-resistant; structure−activity relationship.