In December 2015, Medicines for Malaria Venture (MMV) launched the Pathogen Box, an open-source drug discovery project to stimulate the discovery of drugs for neglected diseases. The box contains 400 diverse drug-like molecules active against neglected diseases of interest, following in the footsteps of MMV’s Open Access Malaria Box. Now, researchers report in the journal mSphere that they have used the box to identify a novel, highly potent antifungal agent with activity against two of the most common fungal pathogens of humans: Cryptococcus neoformans and Candida albicans. image: Pathogen box.
Cryptococcus neoformans and Candida albicans account for 1.4 million infections annually and have mortality rates between 20% and 75%. “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.
Dr. Kronstad said that part of his motivation for focusing on neglected fungi in his laboratory was the outbreak of Cryptococcus gatti on Vancouver Island, British Columbia that began in 1999. Over the past 15 years, British Columbia and the Pacific Northwest of the United States have had some of the largest reported incidences of C. gattii-infections worldwide. Dr. Kronstad’s research, much of it with C. gatti and Cryptococcus neoformans, is aimed at finding mechanisms of virulence, but with an eye to drug development and repurposing drugs against fungal pathogens.
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. 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. 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).
Reporting their findings in the journal mSphere, 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 compounds have activity against microbes, so it is not surprising that activities against fungi would be identified,” said Dr. Kronstad. Diseases targeted by Pathogen Box compounds include buruli ulcer, Chagas disease, cryptosporidiosis, hookworm, malaria, schistosomiasis, 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.
Dr. Kronstad said his laboratory is continuing to study the newly identified compound MMV688271 and pursuing other avenues for discovering new antifungal agents. He is particularly interested in repurposing drugs. For example, the proteasome inhibitor bortezomib (Velcade, Millenium), approved for cancer, has been found to be efficacious against C. neoformans in culture, he said. Other anti-cancer drugs have been found to be useful against fungal pathogens, and one group is currently investigating the efficacy of tamoxifen against Cryptococcosis.
A particular focus of Dr. Kronstad’s lab is targeting iron acquisition, which is critical for the ability of C. neoformans to cause disease in vertebrate hosts. “We are looking at traditional drugs that might be involved in chelating iron or blocking iron availability to the pathogen,” said Dr. Kronstad. His lab is also testing curcumin, from the spice turmeric, which has shown some antifungal activity.
“The pathogen box screening is part of a larger effort to find novel antifungal drugs,” said Dr. Kronstad.