Project: Disrupting drug resistance by exploiting collateral sensitivity to design novel therapeutic strategies for C. auris and C. glabrata

Acronym CycleDrug (Reference Number: JPIAMR2022-052)
Duration 30/12/2022 - 29/12/2025
Project Topic Resistant and tolerant pathogenic fungi are a major medical concern. Candida auris was the first pathogenic fungus officially considered an urgent antimicrobial resistance threat by CDC, and resistant Candida glabrata has been increasing in prevalence over the past decades. Nevertheless, despite their potential for revolutionizing treatment, insights into the evolutionary dynamics of antifungal resistance and tolerance are scarce. Recently, we discovered that C. auris can exhibit collateral sensitivity (CS) and cross resistance (XR). Both phenomena have been studied extensively in tumors and bacteria yet remain unexplored in fungi. Drug cycling and combination therapy strategies designed based on CS and XR networks can prevent or decrease the development of resistance as shown in tumours and prokaryotes. In this project, we will perform an in-depth comparative analysis of CS, XR, drug tolerance and alternative therapies in C. auris and C. glabrata, using antifungal drugs from every class, drugs in clinical development and repurposed agents. Promising schemes will be tested in vivo and across different strains. State-of-the-art techniques, such as next generation sequencing, an in-house optimized CRISPR-Cas9 gene-editing tool and novel labeled antifungal drugs, will be employed to unravel the mechanisms that drive CS and XR at the molecular level. Because the slow process of antifungal drug discovery, the innovative use of existing drugs based on CS and XR holds great promise for the rapid development of new antifungal therapies to fight antifungal resistance.
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Call 2nd JPIAMR-ACTION Joint Call 2022

Project partner

Number Name Role Country
1 Katholieke Universiteit Leuven Coordinator Belgium
2 University Hospitals Leuven Observer Belgium
3 University Hospitals Leuven Observer Belgium
4 Tel Aviv University Partner Israel
5 Institute for Research in Biomedicine Partner Spain
6 Tel Aviv University Partner Israel