Synthesis and Bioactivities of Kanamycin B‑Derived Cationic Amphiphiles

Cationic amphiphiles derived from
aminoglycosides (AGs) have been
shown to exhibit enhanced antimicrobial activity. Through the attachment
of hydrophobic residues such as linear alkyl chains on the AG backbone,
interesting antibacterial and antifungal agents with a novel mechanism
of action have been developed. Herein, we report the design and synthesis
of seven kanamycin B (KANB) derivatives. Their antibacterial and antifungal
activities, along with resistance/enzymatic, hemolytic, and cytotoxicity
assays were also studied. Two of these compounds, with a C12 and C14 aliphatic chain attached at the 6″-position
of KANB through a thioether linkage, exhibited good antibacterial
and antifungal activity, were poorer substrates than KANB for several
AG-modifying enzymes, and could delay the development of resistance
in bacteria and fungi. Also, they were both relatively less hemolytic
than the known membrane targeting antibiotic gramicidin and the known
antifungal agent amphotericin B and were not toxic at their antifungal
MIC values. Their oxidation to sulfones was also demonstrated to have
no effect on their activities. Moreover, they both acted synergistically
with posaconazole, an azole currently used in the treatment of human
fungal infections.