Mycetoma has long been one of the most neglected tropical diseases, affecting the poorest populations in the most remote areas. The disease is a chronic slow-growing infection which comes in either bacterial (actinomycetoma) or fungal (eumycetoma) form. As existing treatments for the fungal form of mycetoma have only a 35% cure rate, amputation is often the only way to save patients.
Associate Professor Wendy van de Sande, from the Medical Microbiology and Infectious Diseases Department at Erasmus University Medical Center (Erasmus MC) based in Rotterdam, Netherlands, has over 20 years of experience in mycetoma research. We spoke to her about the challenging journey of seeking treatment for the disease through the Mycetoma Open Source project (MycetOS), an innovative and unique way of carrying out drug discovery research.
Tell us about MycetOS. When and why was it launched?
MycetOS began towards the end of 2017 with the aim of building a global network of scientists to drive lead optimization of new compounds targeting madurella mycetomatis, the main causative agent of fungal mycetoma. Unfortunately, drug screening for mycetoma is not being done on a large scale. Companies have not put the much-needed effort into finding new drugs for NTDs in general.
The Erasmus MC lab was at the time the only lab screening for antifungal agents, and there was a need to do more to find treatments for mycetoma patients. MycetOS came from the need to research and get more knowledge about treatment molecules and how to get the most effective drug to treat the disease. The molecules are sourced from partner organizations or manufactured by chemists.
MycetOS uses an open source approach to discover new treatments for mycetoma. Open source refers to a transparent working practice where anyone can participate in the project in real time by sharing data and ideas. This means there is a form of shared ownership which ensures that underlying methods and data are public domain.
MycetOS progresses drug discovery efforts through community-driven, in-kind scientific contributions and a robust, fully transparent online presence. All ideas and results are published immediately in real time to an open-access database, free of intellectual property constraints. Using this radically open approach, MycetOS aims to identify potential new treatments in a transparent and inclusive way.
Why is MycetOS important?
Pharmaceutical companies rarely develop novel drugs for skin NTDs, especially mycetoma. There is an urgent need to step into this void. There is currently only one treatment for eumycetoma, theantifungal drug itraconazole that is administered for at least 6 months after which the lesion is surgically removed. To prevent recurrence, at least another 6 months of antifungal treatment is given.
However, the drug is expensive and has considerable side effects. Sadly, a large proportion of patients will get a recurrent infection and eventually amputation is often performed. This situation has caused mycetoma patients to lose jobs, become socially stigmatized and often stop schooling or lose the ability to find a life partner. The bacterial variant of mycetoma can be treated with antibiotics only and does not require surgery.
The objective of MycetOS is to find a new drug for eumycetoma, preferably a drug that will work without the need for surgery and in a relatively shorter time. Although this plan might seem ambitious, it is not impossible.
Who are the partners involved in MycetOS and what is the role of Erasmus MC?
MycetOS is open to anyone willing to participate, including academia, industry, even high school students. Since the beginning, the University of Sydney, University College London, DNDi, Medicines for Malaria Venture (MMV), and Erasmus MC have been core partners. The universities in Sydney and London as well as DNDi design and make new molecules based on the hits we had in the biological evaluation done at Erasmus MC.
This evaluation determines if candidate compounds can inhibit the growth of madurella mycetomatis, and which compounds are the most potent at doing so. The most potent ones are then tested in vivo, in larval models: we infect larvae with the fungus and see which drug compounds are the best at inhibiting the growth of the fungus and therefore at reducing the burden of infection.
Since its inception, what are some of the milestones of the MycetOS project?
We started with 400 compounds and have so far screened 1,200 compounds from three MMV libraries in addition to the fenarimols (compounds from DNDi/Epichem library initially developed for treating Chagas disease) to identify lead compounds. One of the lead compounds was a fenarimol analogue that could inhibit fungal growth.
Furthermore, based on the hits we obtained, additional fenarimols were synthesized by students from the University of Sydney and University College London. We found out that certain chemical properties seemed to be important to be able to penetrate the fungus in vivo. To date, almost 200 fenarimol analogues have been screened.
When we started with the MycetOS project, we solely focused on madurella mycetomatis, which is the main causative agent of mycetoma. Since then, we have included some other causative agents such as falciformispora senegalensis because we found out that there are differences between the causative agents in terms of susceptibility towards different drugs.
This is an important finding and could indicate that before prescribing treatment, proper diagnosis needs to be done to determine which causative agent is causing the disease. In future, it will be important to develop medication that is active against all fungi that cause mycetoma.
What could be the impact of MycetOS on the diagnosis and treatment of mycetoma?
Discovering that different causative agents respond differently to antifungal drugs is crucial, because it means that diagnosing the causative agent correctly is very important when starting mycetoma treatment.
However, the most important outcome of MycetOS is the identification of novel drugs. So far, we have identified very interesting compounds that are already either in use or in clinical trials for other conditions. Among those identified hits are fosravuconazole, the drug currently clinically investigated for mycetoma in Sudan; olorofim, a drug currently in clinical study for other fungal diseases; and fenbendazole, which is used for helminth infections in animals.
Another significant impact of MycetOS on the treatment of mycetoma could be the design of combination therapies, since we have for the first time identified compounds with different modes of action. This was not possible before since all compounds demonstrated to be active previously were acting on the same biochemical pathway.
What could be the impact of MycetOS on mycetoma patients?
MycetOS will allow us to identify more compounds able to treat mycetoma patients. This means that clinicians should in the future have more options to be able to treat the condition. Hopefully this will result in tailor-made treatment for each patient that in turn will hopefully result in shorter treatment durations, eliminate surgeries, and most importantly prevent recurrences.
Are there some notable challenges in the MycetOS project?
Lack of funding is the biggest challenge. All the universities participating are paying from their own resources, which threatens the sustainability of the project.
Furthermore, the fungus madurella mycetomatis is not an easy fungus to work with. It has a slow growth rate that takes up to a week and does not form spores like other fungi. That makes designing an infection model even more challenging. However, with good planning we have managed to get tremendous results in a short time.
When do you think the MycetOS project could lead to available treatment options for mycetoma patients?
This depends on the outcomes of the project. Some of the compounds identified are already approved for other conditions or in clinical trials. They could rapidly progress towards a clinical trial for mycetoma patients, as their safety profiles are already known. However, compounds that are made from scratch in laboratories will take much longer to reach patients.
‘It is wrong that after all this time, we still don’t have a solution for this infection. A solution is possible. All we need to do is find it to end the suffering.’Wendy van de Sande
Photo credit: Abraham Ali-DNDi; Wendy van de Sande