Developing new antifungal therapies against multidrug-resistant fungal pathogens

Fungal infections are an ever-increasing public health challenge, particularly owing to the emergence of Candida auris, which is often contracted in hospitals and remains highly resistant to first-line antifungal agents. Flagged by WHO, this major threat emphasizes the urgent need for new therapeutic solutions while treatment options are limited.

At Université de Montréal, researcher Adnane Sellam is seeking to better understand the mechanisms of fungal virulence to develop more effective and safer treatments against these opportunistic infections, which chiefly affect immunocompromised patients, like people with HIV or cancer, and seniors. To maximize his chances of success in fighting these infections, his interdisciplinary approach combines genomics, microbiology and medicinal chemistry.

The research is focused on three main areas. The first aims to decipher the mechanisms by which pathogenic fungi and specifically Candida albicans infect and reproduce in hosts to identify potential therapeutic targets. The second involves pinpointing new antifungal molecules mainly through high-throughput chemical library screening: a technique that rapidly tests thousands of chemical compounds at the same time. Both avenues have already led to significant discoveries, including the identification of a molecule that is effective in vitro against Candida albicans and Candida auris, as well as the preclinical validation of new antifungals such as aryl-carbohydrazides and halogenated salicylanilides.

Finally, the third area explores the use of intestinal bacteria that antagonize Candida albicans as a therapeutic approach. The hypothesis is that certain bacteria in the intestinal flora may inhibit the fungus’ growth and thus prevent infection in vulnerable patients. This new perspective on the interactions between the microbiota and fungal infections could lead to innovative therapeutic strategies, including the use of antifungal probiotics. Moreover, the work has revealed that some commensal fungi associated with the intestinal flora secrete molecules with endocrine functions, opening a new research pathway into the links between the microbiota and inflammatory diseases.

References

• Tebbji, F., Menon A.C.T., Khemiri, I., St-Cyr, D., Vincent, A.T., et Sellam, A. (2024). Small molecule inhibitors of fungal ∆(9) fatty acid desaturase as antifungal agent against Candida auris. Frontiers in Cellular and Infection Microbiology, vol. 14.  https://doi.org/10.3389/fcimb.2024.1434939
• García, C., Tebbji, F., Daigneault, M., Liu, N., Köhler, J.R., Allen-Vercoe, E., et Sellam, A. (2017). The human gut microbial metabolome modulates fungal growth via TOR signaling pathway. mSphere, 2(6).  doi : 10.1128/mSphere.00555-17
• Henry, M., Khemiri, I., Tebbji, F., Abu-Helu, R., Vincent, A., et Sellam, A. (2024). Manganese homeostasis shapes fitness and virulence of Candida albicans. mSphere, 9(3). doi : 10.1128/msphere.00804-23
• Henry, M., Burgain, A., Tebbji, T., et Sellam, A. (2022). Transcriptional control of hypoxic hyphal growth in the fungal pathogen Candida albicans. Frontiers in Cellular and Infection Microbiology, vol. 11. doi : org/10.3389/fcimb.2021.770478