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Transcriptomic Analysis of Synergy Between Antifungal Drugs and Iron Chelators for Alternative Antifungal Therapies

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Transcriptomic Analysis of Synergy Between Antifungal Drugs and Iron Chelators for Alternative Antifungal Therapies Transcriptomic analysis of synergy between antifungal drugs and iron chelators for alternative antifungal therapies Yu-Wen Lai School of Life and Environmental Sciences (SoLES) Faculty of Science The University of Sydney 2017 A thesis submitted in fulfilment of the requirements of the degree of Doctor of Philosophy. Declaration of originality I certify that this thesis contains no materials which have been accepted for award of any other degree or diploma at any other university. To the best of my knowledge, this thesis is original and contains no material previously published or written by any other person, except where due reference has been made in the text. Yu-Wen Lai August 2016 i Acknowledgements This whole thesis and the years spent into completing it would not have been possible without the help and support of a lot of people. I am thankful and grateful to my supervisor Dee Carter and also to my co-supervisor Sharon Chen for giving me the opportunity to work on this project. I am also thankful to our collaborator Marc Wilkins and his team. This project has been very challenging and your inputs and advice have really helped immensely. A big thank you goes to past and present honours students, PhD candidates and post-docs. Your prep talks, stimulating discussions, humour, baked goods and cider making sessions were my staples for keeping me mostly sane. To Kate Weatherby and Sam Cheung, we started honours and PhDs together and even travelled together in Europe. There were major ups and downs during the course of our projects, but were finally getting to the end! Thank you Katherine Pan and Mia Zeric for always offering chocolate and snacks, I swear I mostly go over to your side of the office just to eat your food. A huge shout out to the people in the Carter Lab, especially to Leona Campbell for letting me cry on your shoulder, tackling any tricky questions I had and letting me know my moments of frustrations with my project were normal in a PhD candidates life. To Majorie Linares for being my writing buddy and helping me with stuff in and outside of my PhD life. To Tien Bui for helping me locate the things I needed and with general lab housekeeping procedures. To Megan Truong for sharing your slices of fruit and helping me with the supervision of other students. To Aidan Kane for helping me with follow up experiments when I was writing. To Christine Dwyer, not just because you were an entertaining honours student when we had you, but there was this one night we were both working late in the lab and I desperately needed to talk to someone as I thought my experiment had gone wrong and I was about to cry and you just happened to be there to listen as I tried to assure myself it was going to be fine. Thank you Igy Pang for supplying me yeast strains and putting up with me when we were analysing humongous datasets. It was a huge learning experience for both of us. Also thank you Nandan Desphande for your help in assembling fungal genome sequences. To the teaching staff who made teaching practicals smooth and enjoyable and tea ladies who always saw me get tea just outside of tea hours. To the anchors of the store, thank you for allowing me to check out huge quantities of lab goods and not say anything when I came back the following week for the same expendables. Also a huge thanks to the workshop guys who fixed our lab equipments. ii I thank my friends outside of uni who kept tabs on me to make sure I was still alive. I want to especially thank Wei for making sure I wouldnt bring my laptop to her birthday lunch otherwise shell feed it to her dog, Malik and Anne for constantly checking Im functioning properly and Bianca for catch up dinners over cider. Finally I need to thank my mum and dad. You encouraged me to do a PhD and thank you for being patient with me during these years. And to my sister, Ive finally finished! iii Abstract There is a growing need to improve the efficacy and range of antifungal drugs. The increase in immunocompromisation among the general population due to old age, infection with imunnosuppressive diseases and immunosuppressive therapies has led to a global increase in fungal infections and invasive fungal diseases. Invasive mycoses are notoriously difficult to treat and are associated with high rates of mortality. The current suite of antifungal drugs are toxic, limited in their spectrum of activity, lacking in target selection and are becoming less effective due to antifungal resistance. For Cryptococcus, which causes debilitating disease and fatal meningo-encepthalitis, the most effective treatment is the combined use of amphotericin B (AMB) and flucytosine (5-FC). However, the toxicity of AMB and the cost of 5-FC makes this combination difficult to implement in resource poor countries where cryptococcosis is highest due to HIV/AIDS. Even in developed countries, resolution of cryptococcosis with AMB+5-FC is difficult and mortality remains high. Alternative anti- cryptococcal therapies are therefore urgently required. Finding and developing new drugs is an expensive and time consuming process, and synergistic therapies that augment current drugs are an alternative approach. Drug synergy enhances the activity of antifungal drugs and improves the clearance of pathogens. It requires less drug, which decreases toxicity, and also slows the development of drug resistance. Iron is important for fungal virulence and pathogenicity and iron chelating agents have been used as antifungal synergents in salvage therapy. However, the mechanistic details of how iron chelators cause synergy are unknown. Advances in genome sequencing technologies and the rise of systems biology allow the cellular responses to antifungal treatments to be studied in detail. It is hypothesised that antifungal-chelator combinations are synergistic in Cryptococcus and that potential antifungal targets can be found by understanding the underlying mechanisms of synergy. This thesis aims to use a transcriptomic approach to understand the mechanistic detail of synergy to find potential antifungal targets. Chapter 3 begins with characterising the interactions of five widely used antifungal drugs (AMB, FLC, itraconazole (ITC), voriconazole (VRC) and caspofungin (CAS)) and a range of iron chelators (EDTA, lactoferrin (LF), ciclopirox olamine (CPO), deferoxamine (DFO), deferiprone (DFP) and deferasirox (DSX). This was performed in Cryptococcus neoformans var. grubii (genotypes VNI and VNII), Cryptococcus neoformans var. neoformans (genotype VNIV) and Cryptococcus gattii (genotype VGII) with a focus on strains with fully sequenced genomes. The S. cerevisiae reference strain S288C was also included to enable a detailed downstream transcriptome analysis. Antifungal-chelator interactions were tested using the CLSI protocol for checkerboard assays. Synergy was found for AMB+LF across all of the yeast strains tested, with LF causing a four- to sixteen-fold reduction in the AMB MIC. iv Supplementation with iron abolished the antifungal activity of LF but did not change the activity of AMB+LF, suggesting that the potentiation of AMB by LF was not solely due to iron chelation. Antagonism was also observed between combinations of azole antifungals and EDTA, DFP and DSX, but this was only seen in C. neoformans var. grubii strains. The results of this chapter showed that diverse responses to antifungal-chelator combinations occur in different Cryptococcus strains and that caution is needed when considering the use of iron chelating agents as synergents for treating cryptococcosis. Transcriptomic analyses of AMB+LF synergy and VRC+EDTA antagonism are presented in Chapter 4. The transcriptomic response to AMB, LF and AMB+LF was first analysed in S. cerevisiae S288C. This provided a detailed platform of gene expression and interaction data for each treatment. Treatment with LF alone did not cause any changes in cellular functions, while AMB alone caused a shutdown of cellular growth processes, up-regulation of various stress responses and activation of the iron regulon via the iron regulating transcription factor Aft1. The addition of LF to AMB caused a down-regulation of stress responses and metal homeostasis, with stress-associated responses that are normally coordinated with zinc regulation via the transcription factor Zap1 dysregulated and the iron regulon shut down. AMB+LF also induced growth-related responses. Together, these data suggested that LF- induced drug synergy was due to disruption of the cells ability to mount an appropriate stress response. The mechanism of synergy differed in C. neoformans H99, where responses to AMB and AMB+LF were similar with an induction of stress responses and repression of cellular growth that were more pronounced in the combined treatment. This increased accumulation of stress following AMB+LF treatment, which resulted from the induction of ER stress, disruption of transmembrane transporter processes and increased metal dysregulation, likely overwhelmed the cells capacity to cope with stress, resulting in accelerated cell death. Despite different underlying mechanisms of AMB+LF synergy in S288C and H99, the disruption of metal ion homeostasis appeared to underlie both processes. This was validated by deleting iron- (Aft1, Cir1 and HapX) and zinc- (Zap1 and Zap104) regulating transcription factors, which resulted in increased AMB susceptibility. Deletion of upstream regulators of these transcription factors and their downstream targets involved in metal homeostasis did not increase AMB susceptibility, however, which suggested that the metal-regulating transcription factors were critical for synergy. Further analysis of drug-binding domains in Zap1 (in S. cerevisiae) and Zap104 (in Cryptococcus) found these proteins to contain druggable sites, which suggested their potential as antifungal drug targets. The mechanistic basis for antagonism was analysed by comparing the transcriptomic responses of VRC+EDTA in C.
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