Research themes
Targets and new therapeutic approaches
Current treatments for fungal infections are limited by antifungal resistance, toxicity and drug interactions. To overcome these limitations, new targets need to be identified for the development of antifungal compounds, which could improve our therapeutic arsenal.
Our work focuses on several converging strategies:
Targeting the interaction between cochaperones and Hsp90 and the calmodulin/calcineurin axis, including Crz1 and FKS.
Targeting the CaPkc1 protein kinase, the protein kinase C involved in MAPK pathways, which regulates cell wall integrity during growth, morphogenesis and the response to parietal stress.
Deciphering resistance mechanisms that may emerge by developing a method for anticipating the emergence of resistance in Candida (CasPER, Cas9-mediated Protein Evolution Reaction).
The use of new tools for addressing active ingredients (self-immolative platforms). These are also being developed to address the problem of antibacterial resistance (ESBL, BMR), particularly in bacteria colonising the intestinal microbiota.
Similarly, current treatments for leishmaniasis face the same limitations as antifungal agents (resistance, toxicity) and are few in number. Our strategy is to build, with our partners (Institut Pasteur, BioCIS, Paris) in the ANR TEXLEISH project, a new line of treatments common to the different species/clinical aspects by developing inhibitors of Leishmania CK1.
Research areas
Line 1:
Hsp90 and cochaperones
The biological validation of the Hsp90/cochaperones models is based on demonstrating the importance of the protein-protein interaction in Candida biology, in particular by exploring its involvement in the maturation of client proteins and exploring the effect of the proposed inhibitors on PPI. The activity of these compounds is evaluated (Fungiline screen platform) on C. albicans and its mutants and in a hip/hop strategy to confirm the mechanism of action.
Collaborators:
A.-S. Castanet, UMR CNRS, Univ. Le Mans - France
A. Laurent, CEISAM, Univ. Nantes - France
J. Jose, Univ. Münster, Germany
C. Gil, Complutense Univ. Madrid, Spain
Line 2:
CaPkc1 pathway
Compounds targeting CaPkc1 (https://pubmed.ncbi.nlm.nih.gov/29853332/) will be evaluated on PKC cascade mutants obtained by site-directed mutagenesis or CRISPR-Cas9 in order to highlight their effects on the MAPK pathway and gain a better understanding of the mechanisms involved in resistance bypass.
Collaboration:
Dr. Florence McCarthy, University College Cork, Ireland
Line 3:
Design of casein kinase 1 (L-CK1.2) inhibitors for the treatment of leishmaniasis
The TEXLEISH consortium (Targeting host-parasite interactions through the inhibition of EXcreted LEISHmania casein kinase 1) is proposing a new paradigm: inhibiting host-parasite interactions by targeting the Leishmania exoproteome, in order to limit the risk of parasite resistance. TEXLEISH is bringing together a wealth of expertise in medicinal chemistry, kinases, parasite biology and in vivo testing to optimise CTN1122 (https://pubmed.ncbi.nlm.nih.gov/26383125/ https://pubmed.ncbi.nlm.nih.gov/33148491/), a potent anti-Leishmania lead compound and L-CK1.2 inhibitor, into a safe and effective orally active drug candidate. This process involves iterative cycles of chemical synthesis, evaluation of efficacy, toxicity, bioavailability in vitro, efficacy in vivo in animal models and mode of action. TEXLEISH will provide a proof of concept to validate the pathogenic exoproteome as the future of targeted strategies. This 4-year project is funded by ANR PRC/Région. https://anr.fr/Projet-ANR-21-CE18-0026.
Collaborations :
Pasteur - Paris and BioCIS UMR CNRS 8076 - Université Paris-Saclay – France
Other themes
The "One Health" approach is a synergistic approach based on the interaction of human, animal and environmental healthcare into a single entity: One Health. We need to improve our knowledge and enrich the current approaches developed by UR 1155 in order to explore our unit's historical models and deal with potentially emerging infections.
Antimicrobial resistance and fungal and bacterial persistence are increasing significantly worldwide and are major public health issues. Dealing with these issues requires integrated, interdisciplinary approaches to understanding the factors that determine the development of these phenomena. Based on the IICiMed laboratory's strategic plan, the Immunity, Microbiota and Persistence theme takes into account the clinical, field and therapeutic targeting data obtained by the "One Health approach to the study of persistence" and “Targets and new therapeutic approaches” themes. The main goal is to explore, in an integrated way, the links between resistance, microbiota and immunity that are associated with the human persistence of fungal pathogens and bacteria, multi- and highly resistant to antibiotics and antifungals.