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Novel Small Molecule Antifungals for Invasive Fungal Infections

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Novel Small Molecule Antifungals for Invasive Fungal Infections University of Kentucky UKnowledge Theses and Dissertations--Pharmacy College of Pharmacy 2020 NOVEL SMALL MOLECULE ANTIFUNGALS FOR INVASIVE FUNGAL INFECTIONS Emily Dennis University of Kentucky, [email protected] Author ORCID Identifier: https://orcid.org/0000-0001-7928-9705 Digital Object Identifier: https://doi.org/10.13023/etd.2020.506 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Dennis, Emily, "NOVEL SMALL MOLECULE ANTIFUNGALS FOR INVASIVE FUNGAL INFECTIONS" (2020). Theses and Dissertations--Pharmacy. 121. https://uknowledge.uky.edu/pharmacy_etds/121 This Doctoral Dissertation is brought to you for free and open access by the College of Pharmacy at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Pharmacy by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies. I retain all other ownership rights to the copyright of my work. I also retain the right to use in future works (such as articles or books) all or part of my work. I understand that I am free to register the copyright to my work. REVIEW, APPROVAL AND ACCEPTANCE The document mentioned above has been reviewed and accepted by the student’s advisor, on behalf of the advisory committee, and by the Director of Graduate Studies (DGS), on behalf of the program; we verify that this is the final, approved version of the student’s thesis including all changes required by the advisory committee. The undersigned agree to abide by the statements above. Emily Dennis, Student Dr. Sylvie Garneau-Tsodikova, Major Professor Dr. David Feola, Director of Graduate Studies NOVEL SMALL MOLECULE ANTIFUNGALS FOR INVASIVE FUNGAL INFECTIONS DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Pharmacy at the University of Kentucky By Emily K. Dennis Lexington, Kentucky Director: Dr. Sylvie Garneau-Tsodikova, Professor of Pharmaceutical Sciences Lexington, Kentucky 2020 Copyright © Emily K. Dennis 2020 https://orcid.org/0000-0001-7928-9705 ABSTRACT OF DISSERTATION NOVEL SMALL MOLECULE ANTIFUNGALS FOR INVASIVE FUNGAL INFECTIONS Human fungal pathogens cause a range of diseases from benign skin conditions (i.e., ringworm) to thrush, mucosal membrane infections, and life-threatening systemic infections including bloodstream infections (i.e., aspergillosis and candidiasis) and Cryptococcal meningitis. These systemic infections occur most often in immunocompromised individuals and have high mortality rates. Current antifungal agents used in the clinic belong to three main classes: the polyenes (e.g., amphotericin B (AmB)), the echinocandins (e.g., caspofungin (CFG)), and the azoles (e.g., fluconazole (FLC)). In addition, the antimetabolite pyrimidine analogue flucytosine is used in combination with AmB. The three main classes class of antifungals each target different aspects of cell wall synthesis or cell membrane function and each class has different strengths and weaknesses depending on the strains of fungi that they are effective against, their route of administration, and their potential side effects. Problems associated with current antifungals include toxicity to patients, only effective against a limited spectrum of fungal strains, and the development of resistance of fungal strains to treatment. Discovering new antifungal therapies is a promising strategy to decrease mortality rates. Herein, three classes of molecules are evaluated for their potential as novel antifungals and reveal that (i) the antihistamines, terfenadine (TERF) and ebastine (EBA) improve the efficacy of azole antifungals when used in combination against a range of Candida strains, (ii) square- planar gold(I)-phosphine complexes exhibit broad-spectrum antifungal activity, and (iii) fluorinated aryl- and heteroaryl-substituted monohydrazones display broad-spectrum activity against fungi with little toxicity to mammalian cells, and (iv) other classes of molecules in recent literature that have shown antifungal activity. This work serves to identify promising scaffolds for novel classes of antifungals with the ultimate goal of bringing newer and more effective antifungals to be used clinically for systemic fungal infections. KEYWORDS: drug synergy, biofilm, drug resistance, Candida, gold complexes, monohydrazone Emily K. Dennis September 29, 2020 Date NOVEL SMALL MOLECULE ANTIFUNGALS FOR INVASIVE FUNGAL INFECTIONS By Emily K. Dennis Sylvie Garneau-Tsodikova Director of Dissertation David J. Feola Director of Graduate Studies September 29, 2020 Date DEDICATION “The education of young people in science is at least as important, maybe more so, than the research itself.” -Glenn T. Seaborg ACKNOWLEDGEMENTS First and foremost, I would like to thank my advisor, Professor Sylvie Garneau-Tsodikova for her mentorship. Sylvie not only helped me become a better scientist at the bench, but also has been wonderful in meeting me where I am and providing helpful nudges to keep me on track. From asking me to sing the ABC’s to get me to project my voice to encouraging me to do SciCats, I thank you for helping me to be a better writer, presenter, and educator as well as a scientist. I would like to thank my committee members Professors Kyung Bo Kim, Jürgen Rohr, H. Peter Spielmann, Oleg V. Tsodikov, and Steven G. Van Lanen for providing thoughtful suggestions and useful feedback on my research projects. I also am very thankful for the letters of recommendation that were written on my behalf. I also want to thank Professor David S. Watt for his collaboration on both the antifungal review featured in Chapter 1, the monohydrazone project presented in Chapter 4, and for writing a letter of recommendation. Similarly, thank you to Professor Samuel G. Awuah and his team for synthesizing the gold complexes studied in Chapter 3. Thank you to the past and present members of the Garneau-Tsodikova and Tsodikov groups for being great colleagues and friends. Thanks to Dr. Sanjib K. Shrestha, Dr. Selina Y.L. Holbrook, and Dr. Huy X. Ngo for sharing their collective wisdom and training me on the various fungal and cell culture techniques. Dr. Nishad Thamban Chandrika and iii Katelyn R. Brubaker, without your synthesized molecules the monohydrazone project of Chapter 4 would not be possible. I would also like to thank Nishad for his help with NMR and chemistry mechanism practice as well as his simple and necessary reminders to take projects one step at a time. I would like to thank Kaitlind C. Howard for working with me to write the antifungal review in Chapter 1. Both Kaitlind and Sylvie dedicated many weekends to working on the review which could have been spent otherwise. I am very happy with how the review paper turned out and I appreciate all their precious time spent working on it. To my two research mentees, Sarah C. Foree and Hannah A. Hilliard, you were a pleasure to work with and Sarah was a welcome help with the MIC assays in Chapter 4. A giant thanks to my friend and colleague, the now Dr. Taylor A. Lundy! It was great being able to go through all the big graduate school landmarks together with you (or a month or two behind you). And thank you for being my person to celebrate the highs with and a shoulder to cry on during the low moments. Another great friend and colleague along this journey has been Dr. Ankita Punetha, who has such a bright smile and great attitude. And finally, Dr. Marina Y. Fosso, Dr. Keith D. Green, and Dr. Caixia Hou, you all have been wonderful colleagues and are always so reliable for being great sources of knowledge and role models. All this research would not be possible without funding. I need to thank the University of Kentucky College of Pharmacy for funding through start-up funds to S.G.-T as well as the 2019-2020 Pharmaceutical Sciences Excellence in Graduate Achievement Fellowship to myself. I have been very fortunate to be able to present my research both in the college and to travel to two conferences in 2019. Travel to conferences was possible with thanks to the iv Peter G. Glavinos, Jr., Ph.D. Travel Award, departmental travel funds, and a travel award from the University of Kentucky Graduate Student Congress which I received. The Department of Pharmaceutical Sciences in the College of Pharmacy has been a wonderful place to work! Thank you to Catina Rossoll for all her hard work keeping everyone else on track and to Dr. Joe Chappell and the AAPS student chapter for affording graduate student trips to places like Eli Lily and other career development events. In addition, within the University of Kentucky, I thank the staff at the counseling center for providing helpful resources to students. Outside of lab, it has been a joy to do Science Cultivates Academically Talented Students (SciCats) with the 3rd grade classes of Tiffany Brown, Kristi Boaz, and Valerie Byrd at Ashland Elementary and the 4th and 5th graders in Bari Douglas’s class at Maxwell Elementary School.
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