The fungal pathogen Candida albicans causes serious infections in immunocompromised individuals, and although treatment is possible using azole or echinocandin drugs, their efficacy can be compromised by the emergence of drug-resistant strains. Writing in Nature Medicine, Wurtele and colleagues show that fungal enzymes that regulate histone acetylation — specifically the acetylation of lysine 56 on histone H3 (H3K56ac) — could be new targets for the treatment of C. albicans infections.

After first showing that H3K56ac in C. albicans is regulated by the RTT109 and HST3 genes, which encode the H3K56 acetyltransferase and deacetylase (Hst3p), respectively, the authors discovered that genetic perturbation of H3K56ac sensitizes C. albicans to genotoxic and antifungal drugs. Both the RTT109 and HST3 gene mutants conferred sensitivity to the genotoxic agents hydroxyurea and methyl methane sulphonate, and the mutant RTT109 strain was highly sensitive to echinocandin drugs. Further work showed that repression of HST3 expression severely impaired proliferation of C. albicans cells, which was due to the high, toxic levels of H3K56ac induced by the repression of HST3, resulting in DNA fragmentation and histone degradation.

As Hst3p is a sirtuin enzyme — a family of NAD+-dependent histone deacetylases that are inhibited by nicotinamide — the authors assessed the effect of nicotinamide treatment on C. albicans proliferation. Addition of nicotinamide to wild-type cells caused an increase in H3K56ac and inhibition of proliferation. Furthermore, several azole-resistant and echinocandin-resistant clinical isolates of C. albicans and other pathogenic fungi, such as Aspergillus fumigatus, were also sensitive to nicotinamide, suggesting that the compound has broad antifungal properties.

Finally, the effect of H3K56ac modulation on C. albicans virulence in A/J mice, which are particularly susceptible to C. albicans infection, was assessed. Repression of HST3 lowered kidney fungal loads and reduced clinical symptoms typical of a C. albicans infection. Nicotinamide given to mice 30 minutes before and 8 hours after infection also lowered kidney fungal loads and alleviated clinical signs of disease progression, which occurred without any obvious modulation of the host's immune response. Furthermore, deletion of RTT109 reduced the virulence of C. albicans in A/J mice.

As the authors note, further in vivo characterization of the effects of nicotinamide are needed. Nevertheless, this study shows that targeting fungal histone acetylation using nicotinamide — which is well tolerated in humans — or future fungal sirtuin inhibitors is a novel strategy to treat C. albicans and possibly other fungal infections.