Inhibition of Histone Modification Process Suppresses Growth of Candida

A team of Canadian microbiologists has identified an enzyme in the medically important yeast Candida albicans that when inhibited by genetic engineering or treatment with nicotinamide (vitamin B3) it reduces the virulence of the fungus and suppresses its growth.

C. albicans is a major fungal pathogen that causes serious systemic and mucosal infections in immunocompromised individuals. In healthy individuals, overgrowth of the fungus causes candidiasis (thrush) of the throat or vagina. "There is an urgent need to develop new therapies to kill C. albicans because it is one of the leading causes of hospital-acquired infections and is associated with high mortality rates,” explained senior author Dr. Martine Raymond, professor of biochemistry at the University of Montreal (Canada).

As part of the effort to devise new ways to suppress C. albicans investigators focused on a process called H3 Lys56 acetylation (H3K56ac), which is an abundant histone modification process regulated by the fungal-specific RTT109 and HST3 genes. Rtt109p encodes the H3K56 acetyltransferase while HST3 encodes the deacetylase (Hst3p).

In a paper published in the July 2010 issue of the journal Nature Medicine, the investigators reported that they had used both genetic engineering techniques as well as treatment with nicotinamide to reduce the level H3K56ac in a population of C. albicans cells. Results showed that these treatments sensitized C. albicans to genotoxic and antifungal agents. Inhibition of Hst3p activity resulted in a loss of cell viability associated with abnormal filamentous growth, histone degradation, and gross aberrations in DNA staining. Furthermore, lowering of H3K56ac levels reduced virulence in a mouse model of C. albicans infection.

Dr. Raymond said, "Although many issues remain to be investigated, the results of our study are very exciting and they constitute an important first step in the development of new therapeutic agents to treat fungal infections without major side effects for patients.”

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