An interdisciplinary partnership against pathogenic fungi
Changed on 17/12/2024
Of the estimated five million species of microscopic fungi in the world, a few hundred pose a risk to humans, and five are of particular concern to Brazilian biologists, due to their impact on public health in South America. To tackle this threat, these scientists have been working for several years with an Inria team, including a Technological Development Action (ADT) launched in 2021.
équipe Capsid
Interdisciplinarity for the benefit of healthcare
Nearly four million Brazilians are affected by serious infections from pathogenic fungi; and over 300 million people worldwide. The issue is all the more alarming because these microscopic fungi are found in our hospitals, where they cause nosocomial diseases, which are particularly dangerous for immunocompromised patients. This is what pushed researchers Bernard Maigret, Marie-Dominique Devignes and Malika Smaïl-Tabbone from the Inria CAPSID project team, a joint undertaking with the University of Lorraine and the CNRS, attached to the Loria laboratory,to respond to the call for projects launched by the CAPES-COFECUB scientific cooperation programme between Brazil and France in 2022, in order to find molecules capable of neutralising these fungi,. "By committing to an interdisciplinary research approach,it takes us out of our comfort zone as we have to deal with knowledge beyond our original areas of expertise," saysMalika Smaïl-Tabonne, the French coordinator of this Franco-Brazilian collaboration. “The research is more time-consuming and harder to evaluate, but it produces conclusive results that are a source of great satisfaction, thanks to both sides adjusting and adapting to each other.”
"Our two teams have been working tirelessly on an innovative project to identify antifungal molecules to treat fungal pathogens, which are a major issue in Latin America and the subject of very limited amount of research. The French team is helping find and improve new treatments for these fungal infections in tropical and subtropical areas. As part of this project, we share our experiences and key information to develop new compounds to treat these serious and underresearched fungal diseases. Maria Sueli Felipe, Brazilian coordinator of the CAPES-COFECUB project
Inhibiting a protein to combat pathogenic fungi
Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, Fonsecaea perdrosoi and Paracoccidioides lutzii. Brazilian biologists have identified five pathogenic fungi that can enter a person's body and cause major infections if they proliferate unchecked. “In the most serious cases, such infections can lead to amputation or even death," says Malika Smaïl-Tabbone. “At present, there are not many antifungal drugs available, and they are specific to a single type of infection.”
So how can we fight against these fungi? “Our aim is to find a molecule that is active against all five species of fungus, so that we can tackle them all at once," says the researcher. “Taking just one drug instead of five greatly simplifies treatment.” A protein called thioredoxin reductasehasbeen identified as a target byBrazilian biologists. This enzyme is essential for the pathogenic fungito grow. If researchers manage to successfully inhibit it, the fungus will die.
Finding the ideal molecule
The challenge is to find a molecule that inhibits the enzyme. And that is what the CAPSID team is working on. It is a long and demanding process, which involves mass screening for molecules that can bind to the target protein and block its action. "To speed up the identification process, we use virtual screening, a technique that involves digitally selecting therapeutic molecules,” says Bernard Maigret. With virtual screening, algorithms are used to sort through millions of molecules according to a series of criteria such as size, toxicity, solubility, ability to be industrially synthesised, etc. This makes the process much faster: a database of ten million molecules can be reduced to a few thousand molecules of interest in just two days.
"However, there is still a tricky stage after that: moleculardocking," says Marie-Dominique Devignes. “This is why we asked Inria to set up an ADT (see inset), in order to streamline the execution of the docking program and the management of the results, so that we can focus on expertly analysing the results.” Docking involves simulating interactions between candidate molecules and thioredoxin to detect whether they can inhibit the enzyme, based on each molecule’s three-dimensional structure and physicochemical properties.
Using generative AI methods
To go even further, researchers are generating more molecules from those that dock correctly. The aim is to optimise research into the most active molecules against the five fungi. The team uses generativeartificial intelligence (AI) methods to produce molecular structures, followed by reinforcement learning.
To date, no fewer than 40 candidate molecules have been isolated. "Overthe next two years, Brazilian biologists will test them in vitro to verify their effectiveness against the five fungi. On our end, we will continue to optimise our research with other molecules selected using generative AI and reinforcement learning methods", says Malika Smaïl-Tabbone. Definitely a scientific collaboration to keep an eye on.
An interdisciplinary team with complementary profiles
Bernard Maigret, Marie-Dominique Devignes and Malika Smaïl-Tabbone have been working together for some 20 years, forming a close-knit group with complementary expertise.
Malika Smaïl-Tabbone
She is a professor and researcher in Computer Science, and the French coordinator of the cooperation project supported by CAPES and COFECUB. Her work led to the discovery of promising candidate molecules against COVID-19, using latest-generation AI techniques combined with molecular docking.
Marie-Dominique Devignes
She is a Bioinformatics researcher and was head of the CAPSID team until July 2024. At the French Bioinformatics Institute, she coordinated a working group on interoperability between computer programs, promoting the FAIR (Findable, Accessible, Interoperable, Reusable) principles for open research data.
Bernard Maigret
He is an emeritus researcher in Theoretical Chemistry, started working on designing therapeutic molecules and the reuse of drugs for new purposes a few years ago. The aim is to reduce the time needed for clinical trials to develop innovative treatments. His research has led to the filing of several patents.
Technological Development Actions (ADT): a whole range of engineering resources for researchers
With a collaborative approach, the Technological Development Action (ADT) set up by Inria has resulted in a virtual screening platform called VSM-G3 (Virtual Screening Manager - Grid Gold Galaxy). This is a shared software infrastructure that enables biologists, chemists and computer scientists to work together effectively to design new treatments, even remotely.
Like all Inria's ADTs, it provides researchers with all the engineering resources they need to carry out their work. Thanks to the expertise of Olivier Demengeon, an engineer in the Experimentation and Development Department of the Inria Centre at the University of Lorraine, the VSM-G3 platform can be used to run the “Gold” docking program on a local computing “Grid” under "Galaxy". The term "Galaxy” refers to a generic environment that can be used to develop academic software platforms that facilitate data analysis and the sharing of computer programs for research. In this way, the VSM-G3 platform is part of an open innovation approach, in line with the European Elixir programme for sharing digital resources and the French Institute of Bioinformatics . The aim is to make it easier for non-IT specialists, in this case the Brazilian biologists, to use complex programs and allow them to focus their efforts on interpreting the results.
