Synergistic effect of eravacycline combined with fluconazole against resistant Candida albicans in vitro and in vivo

The limited availability of antifungal drugs for candidiasis and the persistent problem of drug resistance, necessitates the urgent development of new antifungal drugs and alternative treatment options. This study examined the synergistic antifungal activity of the combination of eravacycline (ERV) and fluconazole (FLC) both <i>in vitro</i> by microdilution checkerboard assay and <i>in vivo</i> by <i>Galleria mellonella</i> model. The underlying synergistic mechanisms of this drug combination was investigated using RNA-sequencing and qPCR. ERV (2 μg/mL) + FLC (0.25–0.5 μg/mL) had strong synergistic antifungal activity against resistant <i>Candida albicans</i> (<i>C. albicans</i>) <i>in vitro</i>, as evidenced by a fractional inhibitory concentration index of 0.0044–0.0088. <i>In vivo</i> experiments in <i>Galleria mellonella</i> larvae infected with resistant <i>C. albicans</i> revealed that ERV (2 μg/larva) + FLC (1 μg/larva) improved survival rates and reduced fungal burden. The results of RNA-sequencing and qPCR showed that the mechanism of synergistic inhibition on resistant <i>C. albicans</i> was related to the inhibition of DNA replication and cell meiosis. These results indicate that the combination of ERV and FLC effectively inhibits resistant <i>C. albicans</i> both <i>in vitro</i> and <i>in vivo</i> and lay the foundation for a potential novel treatment option for candidiasis.