Antifungal Amphiphilic Aminoglycosides

Abstract

The attachment of alkyl and other hydrophobic groups to traditional antibacterial kanamycins and neomycins creates amphiphilic aminoglycosides with altered antimicrobial properties. In this review, we summarize the discovery of amphiphilic kanamycins that are antifungal, but not antibacterial, and that inhibit the growth of fungi by perturbation of plasma membrane functions. With low toxicities against plant and mammalian cells, they appear to specifically target the fungal plasma membrane. These new antifungal agents offer new options for fighting fungal pathogens and are examples of reviving old drugs to confront new therapeutic challenges.

Fig.1

Structure of kanamycin class aminoglycosides

Fig. 2

FG08 suppression of FHB disease in wheat spikelet florets. Florets (one per spikelet) of early flowering heads (cultivar Apogee) were pre-treated with FG08 (10 μL, 5 to 1080 μg mL^-1 followed by inoculation with F. graminearum (F.g.) B4-5A macroconidia (10 μL, 10⁵ conidia mL^-1) 24 h later. (Upper panel) Without FG08 pre-treatment, FHB symptoms (chlorosis and curled spikes) were evident within 4 days, but suppressed with pre-treatment. (Lower panel) Suppression was observed at FG08 concentrations between 5 and 1080 μg mL^-1 with reduced disease incidences between 27 and 82%, respectively. Non-inoculated spikelets had visually healthy florets following FG08 treatments at concentrations ranging between 5 and 1080μg mL^-1. Numbers in the bars indicate the numbers of florets examined (8 to 12 florets per spikelet), and the florets were scored as diseased or not diseased based on visual inspection.

Fig. 3

Structures of amphiphilic neomycin analogues

Fig. 4

FG08 effects on membrane permeability. (A) Addition of FG08 at 30 and 10 μg mL^-1 (10 min) increased the permeability of C. albicans (C. a.) cells and F. graminearum (F. g.) hyphae, respectively, to SYTOX Green (0.2 μM). (B) FG08 was more effective than kanamycin B (kanB) (both with 10 min exposure) in causing SYTOX green dye permeation in C. albicans cells. At 30 μg mL^-1, FG08 was ~12 times more effective than kanamycin B. Triton X100 (1%) gave 100% dye permeation (data not shown). Numbers above the range bars = number of cells analyzed. (C) Neither FG08 (grey bars) or kanamycin B (blank bars) caused hemolysis of sheep erythrocytes at concentrations equal to their antifungal or antibacterial MICs, respectively.

Scheme 1

Glycodiversification synthesis of kanamycin B analogues (compound 1: 3’,4’-di-O-acetyl-1,3,2’6,-tetraazidoneamine

Scheme 2

Direct modification synthesis of kanamycin A analogues

Scheme 3

Synthesis of amphiphilic neomycin analogues