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Fighting fungal infections

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Fighting fungal infections

by Leigh MacMillan

The fungal pathogen Candida albicans causes diseases ranging from topical infections such as athlete’s foot and oral thrush to life-threatening systemic infections. Increasing incidence of infections and drug resistance support the need for new therapeutics.

The protein CYP51 is the major target of drugs used to treat fungal pathogens, but key features of CYP51 that are important for the rational design of new therapeutics have been unclear.

Now, Galina Lepesheva, Ph.D., and colleagues report the catalytic properties, ligand-binding profiles and inhibition of activity of C. albicans CYP51 by clinical antifungal drugs and by an antifungal drug candidate, VT-1161.

The researchers found that the first-line treatment fluconazole was the weakest inhibitor of CYP51 and that posaconazole and VT-1161 were the strongest inhibitors. X-ray structures of C. albicans CYP51 complexes with posaconazole and VT-1161 revealed molecular details that explain the potencies of these drugs.

The findings, reported in the Journal of Biological Chemistry, outline CYP51 features that could direct structure-based development of more efficient antifungal drugs.

This research was supported by the National Institutes of Health (grant GM067871) and in part by Viamet Pharmaceuticals (Durham, NC).

source: Vanderbilt University · Nashville, Tennessee

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