Amphiphilic aminoglycosides

Several aminoglycosides are well-known antibacterial antibiotics. such as streptomycin, kanamycin, and tobramycin . Their long and careless use, however, has led to widespread bacterial resistance and ineffective antibiotics . We focus on the discovery and synthesis of aminoglycosides with new microbial targets and modes of action and that bypass resistance mechanisms. For example, the classical antibiotic kanamycin was chemically altered by adding alkyl chains at various positions around the molecule. Two of these derivatives (FG08 and K20) modified with C8 alkyl groups are less antibacterial, but significantly more fungicidal (Figures 5 and 6) (Chang and Takemoto, 2014). Essentially, antibacterial kanamycins were "switched" into fungicides. With membrane-perturbing and oxidative stress modes of action (vs. protein translation misreading by classical aminoglycosides), FG08 and K20 will be less vulnerable to existing aminoglycoside antibiotic resistance mechanisms. K20, produced in scalable quantities, has shown promise against fusarium head blight - a devastating wheat disease - in recent field trails (Takemoto et al. 2018; Utah State Magazine 2019); Table 1). Improved amphiphilic kanamycin analogs were recently developed for crop protection and animal/human therapeutic applicatons (e.g. Madher et al., 2019; Subedi et. al. 2019).

Figure 5. FG08 and K20 are synthetically derived from kanamycin.

Figure 6. Addition of C8 alkyl group to kanamycin B switches it from an antibacterial into an antifungal. Kanamycin B kills bacteria but not fungi; FG08 kills fungi but not bacteria. (S.a. = Staphylococcus aureus, E.c. = Escherichia coli, S.c. = Saccharomyces cerevisiae, C.c = Cladosporium cladosporiodes

Table 1. K20 as a crop protectant against wheat Fusarium Head Blight