The use of biocides to treat infectious diseases, both in a medical or agricultural context, represents one of the major scientific achievements of the 20th century. However, poor stewardship has resulted in a major crisis that threats not only human health, but also food security worldwide. This is particularly worrisome regarding the recent emergence of highly resistant pathogenic fungi, for which only a very limited number of therapeutic alternatives exist to date. Therefore, finding more sustainable approaches for dealing with fungal pathogens is a pressing need for our society. In this project we propose to use an innovative approach that takes away the focus pathogen control from direct antibiosis. The idea is to apply a more wholesome approach that uses the manipulation of environmental conditions conducive to infection as part of the general response. For this, we propose to use biological interactions and nutritional interference to create a system that deters colonization, allowing for a better reaction of the susceptible host. The simultaneous work on plant and animal models, allows to develop a context-relevant approach that tackles the very topical issue of fungal resistance.

Taking advantage of the knowledge gained in microbial ecology of natural ecosystems (i.e. soils) and extrapolating this to anthropogenic ecosystems constitutes the novelty of this project. The use of trophic interactions is an innovative approach that, in contrast to traditional chemical warfare (i.e. antibiotics and pesticides), might offer a sustainable solution to tackle the worrisome rise of drug resistance in both animal and plant fungal pathogens. We propose to make an innovative application of principles largely accepted in the field of biocontrol of plant pathogens to human health. This comprehensive approach might constitute a more effective way to harness the potential of microbes to improve health and sustainability.
With this project we will be tackling one of the most worrisome threats to human health and food security: the emergence of fungal resistance. Surprisingly, fungal infections have been greatly neglected, in spite of their ubiquity and the cost both in human health (fungal pathogens are estimated to kill 1.5 million people every year) and on agricultural productivity (around 20% yield loses worldwide). The focus on the biotic interactions between fungi and bacteria will be a showcase of alternative mechanisms for the development of a new generation of therapeutic agents that reduce the risk of resistance selection.

We have previously investigated the metabolism of oxalate in soils, where consumption by heterotrophic bacteria is the main sink of oxalate. The relationship between the metabolism of oxalate in soils and improving human and plant health is the foundation of this project. The knowledge gained about oxalotrophy in soils is the stepping stone for the uinvestigating the potential of the host microbiota to regulate oxalate metabolism. To prove the hypothesis of nutritional interference as a deterrent of fungal colonization, we have measured the interaction of oxalogenic fungal (the genera Aspergillus -human-, Botrytis and Sclerotinia -plant-) pathogens with oxalotrophic bacteria. We have demonstrated that oxalotrophic bacteria control the growth at key developmental stages of the pathogen. In addition, we have succeeded in the enrichment of novel spore-forming oxalotrophic bacteria that germinate selectively in response to oxalic acid. The overall results of the confrontation assays support the hypothesis of trophic interaction as a potential venue for controlling the development of opportunistic fungal pathogens.

Fisher, M.C., et al., Worldwide emergence of resistance to antifungal drugs challenges human health and food security. Science, 2018. 360(6390): p. 739-742;
Palmieri, F., Koutsokera, A., Bernasconi, E., Junier, P., von Garnier, C., & N. Ubags. In press. Recent advances in respiratory Aspergillus infections: from lung ecology to therapeutic strategies. Frontiers in Medicine;
Palmieri, F., et al. Oxalic acid, a molecule at the crossroads of bacterial-fungal interactions. Advances in Applied Microbiology, Academic Press. 2019. Adv Appl Microbiol 106;
Palmieri, P., Palmieri, I., Noormamode, N., Estoppey, A., Ishak, M.O., Kelliher, J.M., Vallat, A., Iyer, R., Bindschedler, S., Davenport, K., Chain, P.S.G., Foster Harris, J. & P. Junier. Exploiting oxalotrophic bacteria to control Aspergillus niger lung infections. bioRxiv;
Estoppey, A., Weisskopf, L., Di Francesco, E., Vallat-Michel, A., Bindschedler, S., P.S. Chain & P. Junier. In press. Improved methods to assess the effect of bacteria on germination of fungal spores. FEMS Microbiology Letters.