Fig. 4: Toxicity and in vivo antifungal efficacy of mandimycin.
From: A polyene macrolide targeting phospholipids in the fungal cell membrane
a, Transcription analysis of changes in kidney injury biomarkers in female mice measured 24 h after a single intravenous dose (n = 4 mice per group, two-way ANOVA). Data are mean ± s.d. b, A heat map of kidney histopathological scores (A, tubular cellular casts, cortex; B, tubular cellular casts, medulla; C, tubular degeneration and necrosis, cortex; D, tubular degeneration and necrosis, medulla; E, tubular dilatation, cortex; F, tubular protein casts, cortex; G, tubular protein casts, medulla; H, vascular congestion, bleeding, medulla). c, Haemolysis assay of mandimycin and amphotericin B using defibrated sheep blood. Mandimycin exhibited no obvious haemolysis. d,e, Survival curves (d) and kidney fungal burden (e) after different doses of mandimycin in the neutropenic disseminated candidiasis model of mice infected with MDR C. albicans BNCC 16382 (n = 6 per group for survival curves, n = 3 per group for kidney fungal burden, one-way ANOVA, ***P = 0.0006, ****P < 0.0001). f–h, In vivo antifungal efficacy of mandimycin in the neutropenic thigh-infection mouse model for C. neoformans BNCC 225501 (f) (n = 4 per group, one-way ANOVA, *P = 0.035, **P < 0.0016, ****P < 0.0001) and the skin-infection mouse model (g) and the vaginitis mouse model (h) for C. albicans BNCC 16382 (n = 4 per group, one-way ANOVA, ****P < 0.0001). i, In vivo antifungal efficacy of mandimycin in the neutropenic thigh-infection model of mice infected with amphotericin-B-resistant MDR C. auris AM05 (n = 4 mice per group, one-way ANOVA, **P = 0.0019, ***P = 0.0008, ****P < 0.0001). In all mouse models, the therapeutic compounds and vehicles were administered by subcutaneous injection, and the fungal burden was determined after drug treatment. ISA, isavuconazole; Reza, rezafungin. HC50, concentration needed to cause haemolysis of 50% of the red blood cells.
