Antifungals and the urgent need for biofilm-specific drugs

Last year I had the opportunity to help write a business plan for a startup company that is taking on a very difficult challenge: finding novel antifungal treatments that target the biofilm, rather than free-living, form of fungal infections.

This is important because recent estimates by the NIH indicate that biofilms are responsible for over 80% of all microbial (bacterial and fungal) infections. For both structural and genetic reasons, biofilms are inherently resistant to antimicrobial therapy and host immune defenses.

Systemic biofilm infections are most frequently seeded from biofilms formed on mucosal surfaces or implanted medical devices, such as catheters. In fact, biofilm-based infections on catheters are the most serious and prevalent life-threatening consequence of biofilms, resulting in systemic invasive infections.

Existing antifungal drugs aim to kill C. albicans, a major fungal pathogen of humans, but they have significant disadvantages:

1) Inefficient at eradicating C. albicans existing in the resistant biofilm-form.

2) Disrupt the intricate microbial balance within the gastrointestinal tract, allowing for other microorganisms to flourish.

3) Can cause nephrotoxicity in the dosages required to have some effect on the biofilm.

Current treatments for fungal biofilm-based infections are ineffective at destroying the biofilm reservoir, and novel therapeutics specifically designed to target the biofilm are desperately needed to treat these prevalent infections.

In a ground-breaking 2012 Cell paper, Nobile and colleagues identified the transcriptional network controlling the process of C. Albicans biofilm formation.  It consists of six transcriptional regulators and over 1,000 target genes (40 of which are predicted to be highly druggable).

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