Small-molecule antifungal compound identified for C. albicans

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Researchers have identified a gene-regulating protein termed Bdf1 that appears critical for the survival of Candida albicans. They have suggested this protein may present a future drug target, identifying a dibenzothiazepinone compound that selectively inhibits the protein.

C. albicans can cause severe, life-threatening infections in immunocompromised individuals. This study, published recently in Nature Communications, investigated the possibility of preventing infection by manipulating fungal gene expression. This research may be particularly timely as antifungal resistance is a growing problem, both in the USA and globally.

Senior author, Charles Mckenna (University of Southern California, CA, USA) explained: “When susceptible people develop candida infections, the fungus may enter the bloodstream. If treatment is unsuccessful, it has a very high mortality rate – in the 40% range. We have a very limited number of drugs that are effective in treating such systemic infections. Unfortunately, like many other pathogens, C. albicans is increasingly resistant to the few available drugs, raising the stakes for patients, and fresh approaches are urgently needed.”

The researchers investigated the importance of gene-regulating protein Bdf1, discovering that loss-of-function mutations resulted in a decreased viability in vitro and also reduced fungal virulence in mice.

The team then delved further into how they could inhibit this protein, screening a large library of compounds and reporting small-molecule compounds with promise.

The challenge with drug development is to inhibit the target protein without adversely affecting any human proteins; therefore, the researchers utilized X-ray crystallography to assess the binding modes for these inhibitors, demonstrating the compounds were sterically incompatible with human binding pockets.

The researchers reported a dibenzothiazepinone compound with particular promise – it appeared to selectively inhibit Bdf1 and phenotypically produced the same results as a loss-of-function Bdf1 mutation.

Author Jérôme Govin (University of Grenoble Alpes, France) commented: “The idea is that if you shut down this specific protein, Bdf1, you totally disrupt the whole process of gene expression and it becomes impossible for the fungus to grow. If you knock out the gene that makes the Bdf1 protein, then the fungus doesn’t grow. Moreover, the fungus is no longer virulent when injected into mice.”

McKenna concluded: “We have shown that Bdf1 is an important new target for drug design. Our findings show that compounds that bind to this target will disrupt the growth of the fungus, opening the way to novel drug treatments for fungal disease.”

Sources: Mietton F, Ferri E, Champleboux et al. Selective BET bromodomain inhibition as an antifungal therapeutic strategy. Nat. Comms, 8(15482), doi:10.1038/ncomms15482 (2017); http://news.usc.edu/123220/international-team-uncovers-new-approach-to-combat-deadly-fungal-infection/

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