bekanamycin and Hemolysis

Fluconazole (FLC) is the drug of choice when it comes to treat fungal infections such as invasive candidiasis in humans. However, the widespread use of FLC has resulted in the development of resistance to this drug in various fungal strains and, simultaneously has occasioned the need for new antifungal agents. Herein, we report the synthesis of 27 new FLC derivatives along with their antifungal activity against a panel of 13 clinically relevant fungal strains. We also explore their toxicity against mammalian cells, their hemolytic activity, as well as their mechanism of action. Overall, many of our FLC derivatives exhibited broad-spectrum antifungal activity and all compounds displayed an MIC value of <0.03 μg/mL against at least one of the fungal strains tested. We also found them to be less hemolytic and less cytotoxic to mammalian cells than the FDA approved antifungal agent amphotericin B. Finally, we demonstrated with our best derivative that the mechanism of action of our compounds is the inhibition of the sterol 14α-demethylase enzyme involved in ergosterol biosynthesis.

Topics: Alkylation; Animals; Antifungal Agents; Azoles; Candida albicans; Candidiasis; Cell Line; Ergosterol; Fungi; Hemolysis; Humans; Mice; Microbial Sensitivity Tests; Mycoses

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.

Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Bacteria; Bacterial Infections; Cell Line; Cell Survival; Drug Design; Drug Resistance, Microbial; Fungi; Hemolysis; Humans; Kanamycin; Mice; Mycoses; Surface-Active Agents