Washington, DC - April 12, 2017 - Using the Pathogen Box, an open-source drug discovery project, researchers have identified a novel, highly potent antifungal agent with activity against two of the most common fungal pathogens of humans: Cryptococcus neoformans and Candida albicans. The findings are published this week online in the journal mSphere.
“There is a desperate need for new antifungal drugs and this kind of activity, open source partnership and screening, is a great way to move forward with the discovery of potential new drugs,” said lead author Jim Kronstad, PhD, professor and director of the Michael Smith Laboratories, University of British Columbia, Vancouver, Canada. (image: Pathogen box)
Human fungal pathogens cause over 2 million infections per year and are major drivers of morbidity and mortality. Patients with dysfunctional immune systems, such as those with HIV/AIDS, are particularly susceptible to these pathogens. C. neoformans and C. albicans account for 1.4 million infections annually with mortality rates between 20% and 75%. There are few antifungal drugs available or in the drug pipeline. “Fungal diseases are neglected, particularly compared to those caused by parasites, bacteria, and viruses,” said Dr. Kronstad.
In the new study, Dr. Kronstad and postdoctoral fellow Francois Mayer, PhD, screened the Pathogen Box chemical library for agents with activity against C. neoformans and C. albicans. Modeled on the Malaria Box, the Pathogen Box contains 400 diverse, drug-like molecules active against neglected diseases of interest. The box compounds are supplied in 96-well plates that contain a solution of each compound. In return for the box, which is available for free, researchers are asked to share any data generated in the public domain within two years, creating an open and collaborative forum for neglected diseases drug research. The Pathogen Box is led by Medicines for Malaria Venture (Switzerland).
The researchers identified a highly potent antifungal agent, MMV688271, with activity against both C. neoformans and C. albicans. Preliminary studies suggest the novel compound prevents fungal proliferation by targeting the ability of C. neoformans to withstand stress at the plasma membrane and cell wall.
“The Pathogen Box compounds have already been screened against a whole list of other pathogens and the box has activity against microbes, so it is not surprising that it would have activity against fungi,” said Dr. Kronstad. Diseases targeted by Pathogen Box compounds include buruli ulcer, Chagas disease, cryptosporidiosis, hookworm, malaria, schistomiasis, and tuberculosis.
MMV688271 has previously been shown to have low toxicity for mammalian cells, and thus is an attractive lead compound for further drug development. Future studies will aim to explore the compound’s pharmacokinetics and pharmacodynamics, including interactions with other drugs, synergy with current antifungal drugs, and toxicity.
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