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Bacterial Mechanisms of Toxicity and Resistance to Organoarsenicals

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Bacterial Mechanisms of Toxicity and Resistance to Organoarsenicals Florida International University FIU Digital Commons FIU Electronic Theses and Dissertations University Graduate School 11-13-2020 Bacterial Mechanisms of Toxicity and Resistance to Organoarsenicals Luis D. Garbinski Florida International University, [email protected] Follow this and additional works at: https://digitalcommons.fiu.edu/etd Part of the Biochemistry Commons, Environmental Microbiology and Microbial Ecology Commons, and the Molecular Biology Commons Recommended Citation Garbinski, Luis D., "Bacterial Mechanisms of Toxicity and Resistance to Organoarsenicals" (2020). FIU Electronic Theses and Dissertations. 4549. https://digitalcommons.fiu.edu/etd/4549 This work is brought to you for free and open access by the University Graduate School at FIU Digital Commons. It has been accepted for inclusion in FIU Electronic Theses and Dissertations by an authorized administrator of FIU Digital Commons. For more information, please contact [email protected]. FLORIDA INTERNATIONAL UNIVERSITY Miami, Florida BACTERIAL MECHANISMS OF TOXICITY AND RESISTANCE TO ORGANOARSENICALS A dissertation submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in BIOMEDICAL SCIENCES by Luis D Garbinski 2020 To: Dean Robert Sackstein Herbert Wertheim College of Medicine This dissertation, written by Luis D Garbinski, and entitled Bacterial Mechanisms of Toxicity and Resistance to Organoarsenicals, having been approved in respect to style and intellectual content, is referred to you for judgement. We have read this dissertation and recommend that it be approved. _______________________________________ Irina Agoulnik _______________________________________ Jun-yong Choe _______________________________________ Krishnaswamy Jayachandran _______________________________________ Masafumi Yoshinaga, Co-Major Professor _______________________________________ Barry Rosen, Co-Major Professor Date of Defense: November 11, 2020 The dissertation of Luis D Garbinski is approved. _______________________________________ Dean Robert Sackstein Herbert Wertheim College of Medicine _______________________________________ Andres G. Gil Vice president for Research and economic development And Dean of University Graduate School Florida International University, 2020 ii DEDICATION To my mentors, my family, and my friends who made this possible. iii ACKNOLWEDGMENTS It is difficult to properly thank the many people who have helped me put this dissertation together. Firstly, I want to recognize the efforts, patience, and genuine desire for my success of my advisors, Drs. Barry P. Rosen and Masafumi Yoshinaga. Since I first joined the Rosen lab in 2014 as an undergraduate student, they have dedicated their time and funding to nurture my interest and passion for science. Within the Rosen lab I must also thank Drs. Shashank Pawitwar and Yu Yan, who as Ph.D. students at the time, helped cement my decision to pursue my own Ph.D. and showed me how to succeed in graduate school. I would also like to thank Dr. Jian Chen, who has been a role model for experimental design, productivity, and has been my co-author on several publications. My graduate committee, composed of my two advisors, Dr. Irina Agoulnik, Dr. Krishnaswamy Jayachandran, Dr. Yong Cai, and Dr. Jun-yong Choe, has been instrumental in guiding my research efforts, coursework planning, and ultimately helping me graduate in 4 years. The advice and help of Dr. Alexander Agoulnik and Ms. Odalys De La Rosa were also critical in helping me achieve this goal as director, and coordinator of the graduate program respectively. Lastly, I cannot overstate the support that my parents, Mr. Luis and Mrs. Mercedes Garbinski, and my girlfriend, Ms. Anjali Tripathi have given me. The time that I was able to commit to this dissertation was mostly afforded by their efforts, making sure I am well mentally and physically. In the same vein, my closest friends Messrs. (soon to be Drs.) Abdul Rahim Ansari and Alex Sarracino have also played a major role in this regard. iv ABSTRACT OF THE DISSERTATION BACTERIAL MECHANISMS OF TOXICITY AND RESISTANCE TO ORGANOARSENICALS by Luis D Garbinski Florida International University, 2020 Miami, Florida Professor Barry P. Rosen, Co-Major Professor Professor Masafumi Yoshinaga, Co-Major Professor Arsenic is a toxic element prevalent in the environment since the origin of life on Earth. Bacteria evolved in an arsenic-rich environment, where they developed ways to both overcome arsenic toxicity and harness it to compete with other organisms. These mechanisms include chemical modifications (e.g. oxidation, methylation), degradation, and efflux. The goal of this dissertation is to better characterize these mechanisms, illuminating the arsenic biogeocycle and allowing us to harness organoarsenical toxicity for novel antibiotics. A goal of my research was to elucidate the antibiotic properties of MAs(III), which is synthesized by bacteria to thrive over other bacteria, by identifying cellular targets involved in its toxicity. I identified MurA, a key enzyme in bacterial cell wall synthesis, as a potential target. I determined that MurA is inhibited by organoarsenicals, but not by inorganic As(III), suggesting that these antibiotics kill bacteria by inhibiting cell wall formation. I also determined that MAs(III) inhibits MurA differently than fosfomycin, the conventional MurA-inhibitory antibiotic, highlighting the potential v that organoarsenicals have as antibiotics. The most efficient bacterial resistance mechanism to MAs(III) is efflux from cells, catalyzed by the ArsP permease. While ArsP can transport aromatic organoarsenicals like trivalent roxarsone (Rox(III)), it transports MAs(III) most efficiently. To further characterize ArsP, I probed its substrate binding site by mutagenesis. I found that several conserved residues hypothesized to be required for transport are in fact not required for resistance to organoarsenicals. Furthermore, I determined that the higher affinity of Rox(III) for cysteine pairs does not play a role in selectivity for MAs(III). Aromatic arsenicals are widely used as growth promoters in animal husbandry and understanding their degradation to As(III) by soil bacteria is critical to minimizing their environmental hazards. We characterized their biotransformation by Sinorhizobium meliloti, and identified an enzyme, MdaB, that catalyzes the first step of aromatic organoarsenical degradation. Overall, we show how S. meliloti can activate benign pentavalent aromatic arsenicals into more toxic species. Characterizing enzymes and transporters involved in organoarsenical toxicity and resistance will help us design novel arsenic bioremediation strategies, as well as develop effective arsenic-based antibiotics that will contribute to human health and safety. vi TABLE OF CONTENTS CHAPTER PAGE CHAPTER 1. INTRODUCTION………………………………………………………..1 1.1 Arsenic sources in the environment……………………………………....1 1.2 The duality of arsenic……………………………………………………....2 1.2.1 Arsenic toxicity…….……………………………………..……...2 1.2.2 Arsenic as a medicine…….………………...…………..….......7 1.3 Organoarsenicals and bacterial arsenic biotransformations…...….......9 1.4 Bacterial arsenic transport………………………………………………..12 1.4.1 As(III) efflux systems…………………………………………..13 1.4.2 As(V) efflux systems………………….…………………….....16 1.4.3 Organoarsenical transporters………….……………………..17 1.5 Figures and tables………………………………….…………………..…20 1.6 References…………………………………………………………………22 CHAPTER 2. PROBLEM STATEMENT AND OBJECTIVES……………….........34 2.1 Problem statement……………………………………………......…....…34 2.2 Objectives…………………………………………………………....….....35 2.3 References…………………………………………………………...........35 CHAPTER 3. REDUCTION OF ORGANOARSENICAL HERBICIDES AND ANTIMICROBIAL GROWTH PROMOTERS BY THE LEGUME SYMBIONT SINORHIZOBIUM MELILOTI ……………………………………………………......37 3.1 Introduction………………………………………………………………...37 3.2 Materials and methods……………………………………………………40 3.3 Results……………………………………………...………………………46 3.4 Figures and tables..……………………………………………………….54 3.5 Discussion…………..…………………………………………………......61 3.6 References…………………………………………………………………64 CHAPTER 4. ORGANOARSENICALS INHIBIT BACTERIAL PEPTIDOGLYCAN BIOSYNTHESIS BY TARGETING THE ESSENTIAL ENZYME MurA…………………………………………………………………...……71 4.1 Introduction…………………………………………………………...……71 4.2 Materials and methods……………………………………………………73 4.3 Results……………………………………………………………......…....81 4.4 Figures and tables……..………………………………………………….85 4.5 Discussion……….….……………………………………………...……...92 4.6 References…………………………………………………………………94 CHAPTER 5. A PRELIMINARY STUDY ON THE SUBSTRATE SELECTIVITY OF THE TRIVALENT ORGANOARSENICAL PERMEASE ArsP……………......99 5.1 Introduction…………………………………………………………….......99 vii 5.2 Materials and methods………………………………………….....…....102 5.3 Results and discussion....…………………………………...….....……105 5.4 Figures and tables………………………….……………………………108 5.5 Significance and future directions……...………………………………110 5.6 References…………………………………………………………….....112 CHAPTER 6. SIGNIFICANCE AND FUTURE PROSPECTS…………………...117 6.1 Organoarsenic-based antibiotics……………………………………….117 6.2 Unknown ars genes....………....…....................................................118 6.3 Conclusions and significance………………………………………......119 6.4 References………………………………………………………….........126 VITA…………………..…………………………………………………………….....130 viii LIST OF FIGURES FIGURE PAGE Figure 1. Anthropogenic sources of arsenic and their 20 biotransformations in the environment. Metabolism of organoarsenicals in the body. Figure 2. Oxidation of trivalent organoarsenicals.
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