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Sun Georgetown 0076D 12242.Pdf (4.4MB) HIJACKING THE CANDIDA ALBICANS MULTIDRUG RESISTANT TRANSPORTER MDR1 TO POTENTIATE ANTIFUNGAL ACTIVITY A Dissertation submitted to the Faculty of the Graduate School of Arts and Sciences of Georgetown University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Microbiology and Immunology By Nuo Sun, B.S. Washington, DC April 19, 2013 Copyright 2013 by Nuo Sun All Rights Reserved ii HIJACKING THE CANDIDA ALBICANS MULTIDRUG RESISTANT TRANSPORTER MDR1 TO POTENTIATE ANTIFUNGAL ACTIVITY Nuo Sun, B.S. Thesis Advisor: Richard Calderone, Ph.D. ABSTRACT Fungal invasive infections of humans are now called “hidden killers”. The rising costs of treatment are associated with inappropriate therapy, defined as delayed intervention, inadequate dosage, or administration of an antifungal to which an isolate was considered drug resistant. Treatment failure is commonly due to resistance to triazoles in multi-drug resistant (MDR) fungi. For life-threatening fungal infections, such as those caused by Candida albicans, overexpression of MDR1, which encodes an MDR efflux pump of the major facilitator superfamily, often confers resistance to chemically unrelated substances, including the most commonly used azole antifungals. Further, gain-of-function mutations in the fungal zinc-cluster transcription factor MRR1 are responsible for MDR1 overexpression. I used standardized assays with C. albicans and A. fumigatus to determine berberine susceptibilities. Interestingly, I found that MDR resistant isolates of C. albicans were hypersusceptible to berberine. Strains lacking MDR1 or its transcriptional regulator MRR1 were not hypersusceptible to berberine. I demonstrated that MDR isolates accumulated berberine intracellularly. Microarray comparisons showed an extensive upregulation of MDR1 as well as other importers of the drug: H+ antiporter DHA1 family of polyamine transporters in an azole resistant strain. Substrates of polyamine transporters inhibited berberine activity, and a transporter kinase mutant was resistant to berberine. I propose that these upregulated transporters augment berberine accumulation. A berberine derivative selectively iii accumulated in mitochondria. By Gene Set Enrichment Analysis (GSEA), I found mitochondrial genes were affected by berberine treatment. I then showed biochemically that berberine damages C. albicans mitochondria. This report is the first to demonstrate that overexpression of the MDR1 transporter renders the susceptibility to berberine in C. albicans. As a conclusion, I demonstrate an experimental proof of principle that MDR C. albicans isolates are hypersusceptible to berberine and that berberine accumulates intracellularly via Mdr1p and other transporters. I recommend identifying berberine derivatives that are even more active in treating MDR fungal infections. iv ACKNOWLEDGEMENT MANY MANY THANKS FOR THE CONSTANT LOVE, SUPPORT, HELP AND GUIDANCE MY PARENTS, YUQING SUN AND AIHUA LIU MY WIFE, RONG AN AND HER PARENTS, RUICHENG AN AND BAOHONG WANG MY THESIS MENTOR, DR. RICHARD CALDERONE AND MY COMMITTEE MEMBERS DR. WILLIAM FONZI DR. RONALD CIHLAR DR. R. PAD PADMANABHAN DR. PETER WILLIAMSON AND DR. LIXIN ZHANG DR. JOACHIM MORSCHHÄUSER DR. JAMES LI AND THE CALDERONE LAB MEMBERS DR. DONGMEI LI DR. DEEPU ALEX JARED MAY DR. HUI CHEN DR. FRANCOISE GAY-ANDRIEU AND THE ‘MOMY’ COURSE THE MCGSO RESEARCH GRANT v TABLE OF CONTENTS Chapter I-Introduction .................................................................................................................... 1 1.1 Current status of fungal infections ........................................................................................ 1 1.2 Current therapeutics for treating fungal diseases .................................................................. 2 1.3 Current antifungal drug discovery ......................................................................................... 6 1.4 Antifungal drug resistance .................................................................................................. 13 1.5 Combating Drug Resistant Fungi ........................................................................................ 25 Chapter II-Materials and Methods ................................................................................................ 41 2.1 Strains and strain maintenance ............................................................................................ 41 2.2 Antifungal susceptibility testing .......................................................................................... 41 2.3 Drop plate assays ................................................................................................................. 41 2.4 Drug accumulation assays ................................................................................................... 42 2.5 RNA preparation and microarray ........................................................................................ 42 2.6 Quantitative real-time PCR ................................................................................................. 44 2.7 ROS assays .......................................................................................................................... 44 2.8 Mitochondrial membrane potential ..................................................................................... 45 2.9 Oxygen consumption rate .................................................................................................... 45 2.10 Protoplast and mitochondrial preparations ........................................................................ 46 vi 2.11 Fluorescent staining and microscopy ................................................................................ 48 Chapter III-Results ........................................................................................................................ 49 Part 1: C. albicans overexpressing MDR1 exhibit highly increased susceptibility to a natural product, berberine ...................................................................................................................... 49 3.1.1 Berberine shows broad-spectrum antifungal activity……………………………………...52 3.1.2 C. albicans overexpressing MDR1 is hypersensitive to berberine………………………...55 3.1.3 Inhibition by berberine correlates with intracellular accumulation……………………….58 3.1.4 Berberine activity is facilitated by MDR1 overexpression………………………………..61 Part 2: MRR1 regulation of MDR1 and polyamine transporters confers the hypersusceptibility of berberine ............................................................................................................................... 75 3.2.1 Berberine uptake is regulated by the transcription factor MRR1…………………………..76 3.2.2 Microarray analysis suggest that polyamine transporters may influence berberine activity……………………………………………………………………………………………93 3.2.3 The polyamine transporters………………………………………………………………...98 Part 3: Berberine compromises mitochondria function and induces ROS production .......... 109 3.3.1 Transcriptome analysis demonstrates mitochondrial genes are largely affected by berberine………………………………………………………………………………………..110 3.3.2 GSEA analysis illustrates berberine inhibited and induced gene sets……………………113 3.3.3 Berberine and a related derivative accumulate in mitochondria…………………………121 3.3.4 Berberine impairs mitochondrial functions and induces ROS……………………………126 Conclusion ............................................................................................................................... 138 vii Chapter 4-Discussion .................................................................................................................. 142 Part 1: The specificity of similar quaternary protoberberine alkaloids .................................. 147 Part 2: Are mitochondria potential antifungal targets? .......................................................... 151 Appendix Table 1 Abbreviations……………………………………………………………….165 Appendix Table 2 Strains used in this study…………………………………………………....167 References ................................................................................................................................... 169 viii FIGURES/TABLES Figure 1.1 The ergosterol biosynthetic pathway ..............................................................................4 Table 1 Antifungal drugs ...............................................................................................................7 Figure 1.2 Beta-oxidation, Glyoxylate cycle and TCA cycle in C.albicans ..................................11 Figure 1.3 Structures of selected triazoles ....................................................................................14 Figure 1.4 Stress response pathways that confer azole resistance and tolerance ..........................18 Figure 1.5 Overexpression of the drug transporter MDR1 confers azole resistance ....................23 Figure 1.6 The mitochondrial electron transport chain ................................................................33 Figure 1.7 The growth of wild type and CI mutants of C. albicans are shown with their susceptibilities to fluconazole ......................................................................................................36 Figure 3.1 Structure of berberine ..................................................................................................50 Table 2 Berberine is active against various fungal pathogens ......................................................53 Figure
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