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Natural Strategies for Controlling Virulence and Antibiotic Resistance

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Natural Strategies for Controlling Virulence and Antibiotic Resistance University of Connecticut OpenCommons@UConn Doctoral Dissertations University of Connecticut Graduate School 1-14-2019 Natural Strategies for Controlling Virulence and Antibiotic Resistance in Clostridium difficile Abraham Joseph Pellissery University of Connecticut - Storrs, [email protected] Follow this and additional works at: https://opencommons.uconn.edu/dissertations Recommended Citation Pellissery, Abraham Joseph, "Natural Strategies for Controlling Virulence and Antibiotic Resistance in Clostridium difficile" (2019). Doctoral Dissertations. 2036. https://opencommons.uconn.edu/dissertations/2036 Natural Strategies for Controlling Virulence and Antibiotic Resistance in Clostridium difficile Abraham Joseph Pellissery, PhD University of Connecticut, 2019 Clostridium difficile is a significant enteric pathogen causing a toxin-mediated infection and diarrhea in humans. There has been an increased incidence of C. difficile infection (CDI) in the United States with the emergence of hypervirulent strains and community associated outbreaks. CDI is commonly observed among hospital in-patients undergoing protracted antibiotic therapy, which results in gastrointestinal dysbiosis, creating a conducive environment for spore germination, pathogen colonization in the gut, and subsequent toxin production. An ideal anti- C.difficile therapeutic agent should inhibit critical virulence factors of the pathogen such as toxin production, sporulation and spore germination without inducing gut dysbiosis. Such agents when provided as an adjunct to C. difficile antibiotic therapy could help to improve the clinical outcome of CDI and prevent the relapse of the infection. In this Ph.D. research, the efficacy of three alternative treatment approaches as antivirulence agents was tested for potential future development as therapies against CDI. This included sodium selenite (metalloid), baicalin (flavone glycoside), and selected lactic acid bacteria. All treatment modalities were tested for inhibiting toxin production, sporulation and spore outgrowth in two hypervirulent C. difficile isolates. Moreover, gene expression and cell culture studies were performed to elucidate the anti-toxigenic mechanism of sodium selenite and baicalin. In addition, the effect of sodium selenite in increasing pathogen sensitivity to ciprofloxacin and vancomycin, two common antibiotics used in treating C. difficile, was also tested. Furthermore, the effect of baicalin on CDI was investigated in a mouse model, with special reference to its effect on disease severity and the mouse gut microbiome. The Abraham Joseph Pellissery – University of Connecticut, 2019 results revealed that sub-minimum inhibitory concentration (sub-MIC) and sub-inhibitory concentrations (SIC) of sodium selenite and baicalin, respectively, reduced C. difficile toxin production and cytotoxicity in vitro. In addition, sodium selenite and baicalin inhibited spore outgrowth. Oral supplementation of baicalin improved the clinical outcome in challenged mice, and positively altered the gut microbiome composition. Collectively, these results indicate that the three approaches identified in this study significantly reduced C. difficile virulence, however, follow up validation in animal models for long-term safety and dose standardization, and clinical trials in human subjects are necessary. Natural Strategies for Controlling Virulence and Antibiotic Resistance in Clostridium difficile Abraham Joseph Pellissery B.V.Sc. & A.H., Kerala Agricultural University, 2006 M.V.Sc. Indian Veterinary Research Institute, 2009 A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy at the University of Connecticut 2019 Copyright by Abraham Joseph Pellissery 2019 ii APPROVAL PAGE Doctor of Philosophy Dissertation Natural Strategies for Controlling Virulence and Antibiotic Resistance in Clostridium difficile Presented by Abraham Joseph Pellissery, B.V.Sc. & A.H., M.V.Sc. Major Advisor……………………………………………………………….. Dr. Kumar Venkitanarayanan Associate Advisor………………………………………………………………. Dr. Mary Anne Roshni Amalaradjou Associate Advisor………………………………………………………………. Dr. Dennis J. D’Amico Associate Advisor………………………………………………………………. Dr. Mazhar I. Khan Associate Advisor………………………………………………………………. Dr. Bhushan M. Jayarao University of Connecticut 2019 iii ACKNOWLEDGEMENTS I would like to express my gratitude and immense respect to my major advisor, Dr. Kumar Venkitanarayanan, for his continual guidance and support throughout my tenure as a graduate student. I consider myself so blessed and privileged to have got the opportunity to work under the able tutelage of such an enthusiastic and hard-working researcher. The experiences that I gained from his lab helped me to evolve as an independent researcher and a critical theorist in the microbial sciences. I would like to express my sincere gratitude to my associate advisors, Dr. Mary Anne Amalaradjou, Dr. Dennis D’Amico, Dr. Mazhar Khan and Dr. Bhushan Jayarao for their continuous encouragement, critical advice and suggestions throughout my doctoral research. I would also like to extend my gratitude to all the Faculty, graduate students and administrative staff of the UConn Animal Science department for all the help and support provided to me during my life here as a doctoral student. My sincerest and profound gratitude to my dear friends: Ajith, Shafeekh, Sambhu, Shaan, Bindu, Elza, Deepa and Poonam for your camaraderie during the sunny and rainy days of my student life at UConn. Words are not enough to express my gratitude to my mother, Mrs. Mary Joseph and my parents-in-law, Mr. Anto E.V. and Mrs. Lissy Varghese for their unfailing support and prayers when I needed it the most. I remember and thank my father, Late Mr. P. C. Joseph for all the love, care, support and blessings that he has provided me I am sure that my father would be proud of me on my achievement up in heaven. I am grateful to my siblings James and Teresa, my in-laws Tina, Annlyn, Manu, Sharon and Arun, and my nieces and nephew, Sarah, Rahael and Gabriel: for all their heartwarming kindness and support. iv I would like to express my deepest love and thanks to my daughters Annarita and Helenna for their laughter, naughtiness, kisses and hugs that magically made my rough days much better. I also want to thank my wife Liya, for her wonderful companionship, understanding, patience and love throughout the last eight years. Lastly, I thank the Almighty for strengthening me to successfully complete my endeavor as a doctoral student and for all the blessings showered upon me throughout my life. v TABLE OF CONTENTS Approval page…………………………………………………………………………... iii Acknowledgments…………………………..………………………………………..... iv Table of Contents……………………………………………………………………….. vi List of figures…………………………………………………………………………… xii List of tables……………………………………………………………………………. xv List of abbreviations……………………………………………………………………. xvi Chapter I: Introduction………………………………………………………………. 1 Chapter II: Review of literature……………………………………………………… 7 1. Clostridium difficile or Clostridioides difficile (CD)…………………………....……… 8 1.1.Epidemiology of CDI…………………………………...………………………………… 10 1.2.Clinical manifestations and risk factors associated with CDI in humans…..…….. 14 1.3.Pathogenesis of CDI………………………………..…………………………..………... 15 1.4.C. difficile toxins…………………………………………………………………….……. 17 1.5. Non-toxin associated virulence factors initiating host colonization..…………… 20 1.6. C. difficile sporulation ………………………………………………………………… 21 1.7. C. difficile spore germination………….……………………………………………… 23 1.8. Influence of gut microbiome on CDI susceptibility.………………………………… 24 2. Antimicrobial resistance in C. difficile…..……………………………………………… 26 3. Treatment approaches for human CDI…………………………………………………… 27 3.1. Current and novel antimicrobials for CDI…….…………………………….….. 29 3.2. Alternate and emerging treatment strategies for CDI..……………………………. 29 3.2.1. Immunization strategies…………………………………………………………... 29 vi 3.2.2. Fecal microbiota transplantation……………………………………………….. 30 3.2.3. Non-toxigenic strains of C. difficile……………………………………………... 30 3.2.4. Emerging strategies for CDI therapy….………………………………………… 31 4. Metals 32 5. Phytochemicals 34 6. Probiotic therapy 36 References………………………………………………………………………………………… 39 Chapter III: In vitro efficacy of sodium selenite on toxin production, spore outgrowth and antibiotic resistance in hypervirulent Clostridium difficile….…….. 60 Abstract…………………………………………………………………………………. 61 1. Introduction…………………………………………………………………………... 62 2. Materials and Methods……………………………………………………………….. 63 2.1. Bacterial isolates and culture conditions……..……………………………………... 63 2.2. Establishment of sub-minimum inhibitory concentration and minimum inhibitory concentration of sodium selenite and antibiotics ………………………………. 64 2.3. Effect of sodium selenite on C. difficile Toxin Production and Cytotoxicity…… 65 2.4. ELISA for Total Toxin A and B……………………………………………………….. 65 2.5. Cytotoxicity Assay………………………………………………………………………. 66 2.6. Real-Time Quantitative PCR (RT-qPCR)….………………………………………… 66 2.7. Effect of sodium selenite on C. difficile spore germination and outgrowth….….. 67 2.8. Effect of sodium selenite on antibiotic resistance in C. difficile….………………. 68 2.9. Statistical analysis…..………………………………………………………………….. 68 3. Results………………………………….………………………………………………….. 68 vii 3.1. Sub-minimum inhibitory concentrations and minimum inhibitory concentrations of sodium selenite and antibiotics…………………………...……………… 68 3.2. Effect of selenium on C. difficile toxin production……………………………………
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