Extended Data Fig. 7: Combining C2’epimerization and C16 amidation results in a renal sparing potent antifungal.
From: Tuning sterol extraction kinetics yields a renal-sparing polyene antifungal
a. in vitro efficacy of potent AmB-amides. Head-to head comparison of in vitro toxicity of AmB, C2’epiAmB, AM-243-2 and AM-2-19 against b, H9C2 cells (rat cardiomyocyte; n = 3 biological replicates/conc.) c, Hep-G2 cells (human liver cell; n = 3 biological replicates/conc.) d, K562 (human red blood cells progenitors; n = 3 biological replicates/conc.) e, SHSY-5Y (human neural blastoma; n = 3 biological replicates/conc.) and f, RPTEC (primary renal proximal tubule epithelial cells; n = 3 biological replicates/conc.). C2’epiAmB and AM-2-19 both g, do not lyse human red blood cells (n = 3 biological replicate/conc.), and h, retain an AmB-like drug-drug interaction profile and i, do not elevate kidney injury biomarkers after 24 h of single IV 45 mg/kg dose (n = 4 mice/group). Pairwise statistical analyses were performed using two-way ANOVA with Tukey’s multiple comparison test; **P = 0.0022, ****P < 0.0001. AM-2-19 binds j, ergosterol but not k, cholesterol in the UV-Vis binding assay and is l, highly efficacious against pathogens that were resistant to C2’epiAmB (100% inhibition reported). m, Comparison of solution stability between AM-2-19 and C2’deOAmB in PBS buffer at pH 6. Pairwise two-way ANOVA with Tukey’s multiple comparison tests was performed at each time point; ***P = 0.0005, ****P < 0.0001. AM-2-19 does not bind n, lanosterol, o, zymosterol, and shows little to no binding with p, episterol. q, Head-to-head in vitro efficacy comparison between AM-2-19, C2’deOAmB, Natamycin and Nystatin. Data in j and k are representative of at least 3 independent experiments.
