Aprosamine Derivatives Active against Multidrug-Resistant Gram-Negative Bacteria.

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.