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Copyright by Natalie Kay Boyd 2020 the Dissertation Committee for Natalie Kay Boyd Certifies That This Is the Approved Version of the Following Dissertation Copyright by Natalie Kay Boyd 2020 The Dissertation Committee for Natalie Kay Boyd Certifies that this is the approved version of the following dissertation: THE IN VITRO ANTIBIOTIC ACTIVITY OF NON-ANTIBIOTIC DRUGS AGAINST S. AUREUS CLINICAL STRAINS Committee: Christopher R. Frei, Supervisor Kelly R. Reveles Jim M. Koeller Jose L. Lopez-Ribot Manjunath P. Pai THE IN VITRO ANTIBIOTIC ACTIVITY OF NON-ANTIBIOTIC DRUGS AGAINST S. AUREUS CLINICAL STRAINS by Natalie Kay Boyd Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas at Austin August 2020 Dedication I dedicated this dissertation to my family, friends, and colleagues, who have supported and loved me unconditionally. Abstract THE IN VITRO ANTIBIOTIC ACTIVITY OF NON-ANTIBIOTIC DRUGS AGAINST S. AUREUS CLINICAL STRAINS Natalie Kay Boyd, Ph.D. The University of Texas at Austin, 2020 Supervisor: Christopher R. Frei Drug repurposing, or identifying new uses for existing drugs, has emerged as an alternative to traditional drug discovery processes involving de novo synthesis. Drugs that are currently approved or under development for non- antibiotic indications may possess antibiotic properties, and therefore may have repurposing potential, either alone or in combination with an antibiotic. They might also serve as “antibiotic adjuvants” to enhance the activity of certain antibiotics. The objective of the proposed research is to utilize novel screening tools to characterize antibiotic effects of select non-antibiotic drugs against Staphylococcus aureus clinical isolates. We hypothesized that one or more of the non-antibiotic candidates selected for this study would demonstrate antibiotic activity against Staphylococcus aureus, either directly (as monotherapy) or indirectly (in combination with antibiotic drugs). We determined minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) for non-antibiotic drugs (amlodipine, v azelastine, ebselen, and sertraline) against five clinical Staphylococcus aureus isolates and one quality control strain using microplate alamar blue assays. Clinical isolates were selected from previous clinical and epidemiological studies by our research group. These isolates were obtained from wound swab cultures of patients with skin and soft tissue infections (SSTIs) who were seen at primary care clinics in the South Texas Ambulatory Research Network (STARNet) from 2010 to 2013. Our group had previously identified resistance genes and determined susceptibilities in these isolates using whole genome sequencing and Vitek 2 automated testing system (bioMerieux, Durham, NC), respectively. Each clinical isolate was genetically and phenotypically distinct from one another. Amlodipine, azelastine, and sertraline MICs were 64 µg/ml (112 µM), 200 µg/ml (480 µM), and 20 µg/ml (60 µM), respectively, while ebselen ranged from 0.25 - 1 µg/ml (1 - 4µM). MBCs for amlodipine, azelastine, sertraline, were within one dilution of their MICs, indicating bactericidal activity for all test isolates. Ebselen MICs were 1 - 2 dilutions higher in isolates carrying two or more resistant determinants. Though the microplate reader has the capability of continuous monitoring of fluorometric data, this functionality was limited in this case due to significant evaporation, likely from absence of the microplate lid during incubation. Evaporation was immediately evident upon visual inspection, as the volume loss created a more pale or colorless appearance. Not surprisingly, volume loss from evaporation also affected antibiotic concentrations, which gave the appearance of increased potency. We observed this with the control strain after measuring fluorescence activity over 16 hours against non-antibiotics. Azelastine 100 µg/ml and sertraline 10 µg/ml appeared to inhibit growth by more than 60% compared to vi the control. However, azelastine and sertraline MICs, determined prior to this experiment, were shown to be one dilution higher at 200 µg/ml and 20 µg/ml, respectively. Therefore, it less plausible that azelastine and sertraline inhibited growth to this extent at sub-MIC concentrations. The overall level of fluorescence intensity, when tested as part of continuous monitoring, was also at least 30% lower than expected compared to initial testing for signal to background ratio. These inconsistencies can easily be explained by evaporation. Dose-response curves for non-antibiotics were plotted by drug concentration (log [µg/ml]) and % inhibition. Calculated IC50 ranges were 37.9 - 47.2 µg/ml (66.3 - 82.6 µM) for amlodipine, 116 - 119 µg/ml (278 - 286 µM) for azelastine, 11.7 - 18.3 µg/ml (35.1 - 54.9 µM) for sertraline, and 0.17 - 0.62 µg/ml (0.67 to 2.5 µM) for ebselen. In summary, all four non-antibiotics demonstrated in vitro activity to varying degrees against S. aureus clinical isolates. Ebselen was the most potent of the four non-antibiotics tested, with MICs between 0.25 to 1 µg/ml, and MBC/MIC ratios of 1-2. This range is consistent with what prior investigations have observed against S. aureus. In fact, ebselen has demonstrated bactericidal activity various multidrug resistant strains of S. aureus, including vancomycin-intermediate and vancomycin-resistant strains. Additionally, ebselen has been shown to inhibit toxin production as well as biofilm formation. When viewed in the context of available literature, these data suggest that the non-antibiotic candidates selected for this study might have future potential as antibiotics or antibiotic adjuvants. vii Table of Contents Chapter One. Drug repurposing for antibiotic development................ 1 Drug discovery: Overview of process ................................................. 1 Antibiotic drug development: A historical perspective ........................ 3 Penicillin: A landmark 'bench to bedside' breakthrough ............. 3 The antibiotic era ....................................................................... 5 Antibiotic innovation gap ............................................................ 7 Emergence of resistance ......................................................... 17 Staphylococcus aureus - an urgent threat ............................... 19 Addressing the unmet clinical need ................................................. 21 Drug repurposing ............................................................................. 24 Overview .................................................................................. 24 Non-antibiotics ......................................................................... 28 Antibiotic adjuvants .................................................................. 31 References ...................................................................................... 33 Chapter Two. The in vitro activity of non-antibiotic drugs against Staphylococcus aureus clinical strains ....................................... 44 Introduction ...................................................................................... 44 Central Hypothesis, Specific Aim, and Objectives ........................... 45 Central Hypothesis .................................................................. 45 Specific Aim ............................................................................. 46 Methods and rationale ..................................................................... 46 Staphylococcus aureus isolates ............................................... 46 Selection of non-antibiotic drug candidates ............................. 47 Non-antibiotic drugs: Solubility and storage ............................. 49 Selection of non-antibiotic drug concentrations ....................... 50 Antibiotic susceptibility testing ................................................. 51 Data analysis ........................................................................... 54 Assay optimization ................................................................... 54 viii Results ............................................................................................. 56 Assay optimization ................................................................... 56 Non-antibiotic susceptibilities ................................................... 56 Fluorometric analysis ............................................................... 57 Discussion and Conclusion .............................................................. 61 Limitations ........................................................................................ 65 References ...................................................................................... 66 Chapter Three. Translational application ............................................ 72 References ...................................................................................... 76 Appendices ............................................................................................ 77 Appendix A ...................................................................................... 77 Appendix B ...................................................................................... 78 Appendix C ...................................................................................... 79 Appendix D ...................................................................................... 80 Bibliography ........................................................................................... 81 ix
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