Novel Cell-Killing Mechanisms of Hydroxyurea and the Implication toward Combination Therapy for the Treatment of Fungal Infections

We have previously reported that anerg11 mutation affecting ergosterol synthesis and ahem13 mutation in the heme synthesis pathway significantly sensitize the fission yeastSchizosaccharomyces pombe to hydroxyurea (HU) (1, 2). Here we show that treatment with inhibitors of Erg11 and heme biosynthesis phenocopies the two mutations in sensitizing wild-type cells to HU. Importantly, HU synergistically interacts with the heme biosynthesis inhibitor sampangine and several Erg11 inhibitors, the antifungal azoles, in causing cell lethality. Since the synergistic drug interactions are also observed in the phylogenetically divergentSaccharomyces cerevisiae and the opportunistic fungal pathogenCandida albicans , the synergism is likely conserved in eukaryotes. Interestingly, our genetic data forS. pombe has also led to the discovery of a robust synergism between sampangine and the azoles inC. albicans . Thus, combinations of HU, sampangine, and the azoles can be further studied as a new method for the treatment of fungal infections.