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Compound BT-08 and high molecular weight antibiotics act synergistically in vivo and in vitro. (A) Activity of rifampicin (RIF) and BT-08 and their combinations in the zebrafish embryo infection model. Zebrafish embryos were yolk-infected with M. marinum expressing tdTomato, and treatment was performed by immersion. Each data point represents the integrated red fluorescence intensity of a single zebrafish embryo, and the signal of each group is expressed as the mean ± SD of the mean. CTL represents the non-infected group. The fold difference between the means of different treatment groups is depicted. Statistical significance was determined by one-way ANOVA, following Tukey’s multiple comparison test by comparing each treatment group with the rest (****P ≤ 0.0001). CTL represents the non-infected group. (B) Representative images of M. marinum yolk-infected zebrafish embryos treated with DMSO, BT-08 at 3 μM, RIF at 3 μM, or their combination (BT-08 at 3 μM and RIF at 3 μM) at 4 d post-fertilization. The red color corresponds to a signal from M. marinum expressing tdTomato, and the green color corresponds to the injection control dye fluorescein. The scale bar represents 500 μm. (C) Drug combinations between BT-08 and selected antibiotics reported as the fractional inhibitory concentration (FIC) and the FIC index (FICI) were investigated in M. marinum using a checkerboard assay using the HdB medium with Tween-80. (D) FICI of BT-08 and selected antibiotics calculated using a checkerboard assay in M. marinum (HdB medium with Tween-80) is plotted against the molecular weight (g/mol) of tested antibiotics. The correlation was evaluated using Spearman’s one-tailed correlation test, showing significance of P = 0.0315.
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