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. Author manuscript; available in PMC: 2024 Feb 22.
Published in final edited form as: Nature. 2023 Nov 8;623(7989):1079–1085. doi: 10.1038/s41586-023-06710-4

Extended Data Fig. 8 ∣. AM-2-19_DP2K is highly efficacious and resistance evasive.

Extended Data Fig. 8 ∣

a, Representative examples of several drug-resistant strains that are susceptible to AM-2-19_DP2K treatment, unlike its comparators. The study was conducted at UT Health, San Antonio, and 100% inhibition was reported. b, AM-2-19_DP2K is highly efficacious against hundreds of clinical fungal isolates tested at different locations (number of isolates in parenthesis; 100% inhibition reported). For AM-2-19_DP2K and comparators, dosing concentrations (μM and μg/ml) are reported based on the active pharmaceutical ingredient (API). The MIC values of DSG-PEG 2000 (DP2K), tested at UIUC, were >16 μM against all isolates. AmB or AmBisome® is used as a comparator because, unlike AM-2-19, AmB does not form a homogenous solution with DSG-PEG 2000. c, in vivo efficacy of AM-2-19_DP2K and comparator AmBisome® was evaluated in male CD-1 non-neutropenic disseminated candidiasis model infected with C. albicans SC5314 after 7 days of daily IV dosing (n = 6 mice/group). Pairwise statistical analyses were performed using one-way ANOVA with Tukey’s multiple comparison test; ***P = 0.0008, ****p < 0.0001. Dose dependent mitigation of fungal burden on day 4 in neutropenic mucormycosis model, infected with R. delemar (first dose 48 h post infection; q24h; n = 10 mice/group) was measured by qPCR for d, lung (one-way ANOVA with Tukey’s multiple comparison test; ****P < 0.0001) and e, brain tissues (one-way ANOVA with Tukey’s multiple comparison test; ****P < 0.0001). f, Gross pathology, and histological examination of lung tissues harvested from mice infected with R. delemar, and treated with placebo, AM-2-19_DP2K or AmBisome®. Notice the diffused filamentation in the lung from placebo or 0.3 mg/kg of AM-2-19_DP2K treated mice. Fewer/no hyphae are evident in lungs of mice treated with AM-2-19_DP2K 1.5, 7.5 and 30 mg/kg or AmBisome®. Arrows in upper panel refer to fungal abscesses. Scale bar 100 μm for histopathological analysis (bottom). Tissue fungal burden of g, lungs (one-way ANOVA with Tukey’s multiple comparison test; *P = 0.0147, ****P < 0.0001) and h, brain (one-way ANOVA with Tukey’s multiple comparison test; *p = 0.0243, ****P < 0.0001) of mice (n = 10 mice/group) infected with M. circinelloides, treated with either drug and euthanized on Day +4 post infection. Spontaneous mutation frequency study indicates AmBisome-like resistance-refractory property of AM-2-19_DP2K against i, C. tropicalis ATCC 90874, j, C. albicans ATCC90028 k, C. glabrata ATCC 90030 and l, C. krusei ATCC 6258 after 20 passage and MIC recorded after every three passages. All dosing units are mg/kg. In mice, fungal burdens below the limit of detection (LOD) were given a nominal value CFU/g = 1. Results are means ± SD. In mice, fungal burdens below the limit of detection (LOD) were given a nominal value of CFU/g = 1.