Disrupting drug resistance by exploiting collateral sensitivity to design novel therapeutic strategies for C. auris and C. glabrata
( CycleDrug )
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.
- Patrick Van Dijck, Katholieke Universiteit Leuven, Belgium (Coordinator)
- Katrien Lagrou, University Hospitals Leuven, Belgium (Observer)
- Johan Maertens, University Hospitals Leuven, Belgium (Observer)
- Micha Fridman, Tel-Aviv University, Israel (Partner)
- Juan Antonio Gabaldon Estevan, Institute for Research in Biomedicine, Spain (Partner)
- Berman Judith, Tel-Aviv University, Israel (Partner)
Multidrug resistance is a major problem in Candida auris, the first pathogenic fungus officially considered an urgent antimicrobial resistance threat by the CDC, and in Candida glabrata, which accounts for 20-40% of all systemic Candida infections. Antifungal resistance often leads to treatment failure, which significantly reduces survival rates of lethal candidiasis. Meanwhile, the antifungal drug market comprises only four classes. By evolving C. auris and C. glabrata in different drugs and mapping their responses to other drugs, we have discovered collateral sensitivity (CS) and cross resistance (XR). CS is the process in which the acquisition of drug resistance towards one drug, confers an increased sensitivity towards another drug. Conversely, XR confers reduced susceptibility to more than one drug upon exposure to one drug. Information regarding the evolutionary tendencies of pathogenic fungi can be leveraged to improve therapeutic approaches for treating fungal infections. Both CS and XR have been studied extensively in tumors and in bacteria, but remain unexplored in fungi. In this study, we will explore novel treatment schemes that have the potential to prevent the development of antifungal drug resistance in MDR species of most concern: C. auris and C. glabrata.