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Discovery of New Antimicrobial Agents Using Combinatorial Chemistry

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Discovery of New Antimicrobial Agents Using Combinatorial Chemistry Wright State University CORE Scholar Browse all Theses and Dissertations Theses and Dissertations 2007 Discovery of New Antimicrobial Agents using Combinatorial Chemistry William I. Northern Wright State University Follow this and additional works at: https://corescholar.libraries.wright.edu/etd_all Part of the Immunology and Infectious Disease Commons, and the Microbiology Commons Repository Citation Northern, William I., "Discovery of New Antimicrobial Agents using Combinatorial Chemistry" (2007). Browse all Theses and Dissertations. 206. https://corescholar.libraries.wright.edu/etd_all/206 This Thesis is brought to you for free and open access by the Theses and Dissertations at CORE Scholar. It has been accepted for inclusion in Browse all Theses and Dissertations by an authorized administrator of CORE Scholar. For more information, please contact [email protected]. DISCOVERY OF NEW ANTIMICROBIAL AGENTS USING COMBINATORIAL CHEMISTRY A thesis submitted in partial fulfillment Of the requirements for the degree of Master of Science By WILLIAM ISAAC NORTHERN B.S., University of Cincinnati, 1982 2007 Wright State University WRIGHT STATE UNIVERSITY SCHOOL OF GRADUATE STUDIES October 29, 2007 I HEREBY RECOMMEND THAT THE THESIS PREPAIRED UNDER MY SUPERVISION BY William Isaac Northern ENTITLED Discovery of New Antimicrobial Agents Using Combinatorial Chemistry BE ACCEPTED IN PARTIAL FULFULLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science ______________________________ Nancy Bigley, Ph.D. Thesis Director ______________________________ Barbara Hull, Ph.D. Department Chair Committee on Final Examination ______________________________ Nancy Bigley. Ph.D. ______________________________ Barbara Hull, Ph.D. ______________________________ Daniel Ketcha, Ph.D. ______________________________ Gerald Alter, Ph.D. ______________________________ Joseph F. Thomas, Jr., Ph.D. Dean, School of Graduate Studies ABSTRACT Northern, William Isaac. M.S., Department of Biological Sciences, Wright State University, 2007. Discovery of New Antimicrobial Agents Using Combinatorial Chemistry Combinatorial chemistry has become an important aspect of medicinal research due to its flexibility and the ability to produce large numbers of potential therapeutic agents. Once compounds are made, they must be screened to determine if there is any biological activity. This research project focused on developing a screening method for chemical agents produced by a graduate student in the chemistry department at Wright State University. After an acceptable screening method was found, the goal of the project was to determine if compounds produced had either antibacterial activity, antifungal activity, or both. Seven compounds exhibited biological activity. Two of these compounds had activity against all organisms tested. Five compounds had activity against only Staphylococcus aureus. Also, initial toxicity studies were performed on the two compounds that had activity against both bacteria and fungi. The toxicity was detected by cytopathic effect (CPE) noted in human and monkey cell lines. One compound demonstrated severe toxicity while the other compound demonstrated slight toxicity. Additional research, including animal safety studies, will be required to determine if these compounds are viable prospects for development into antimicrobial agents. This research confirmed that it is possible to use combinatorial methods to produce agents. However, the ability to produce antimicrobial compounds is only a small part of producing a useful drug. iii TABLE OF CONTENTS Page I. INTRODUCTION . 1 Importance of Finding New Antimicrobials . 1 Historical Perspective . 4 Sources of New Antibiotics . 6 Natural Products . 6 Bacteria and Fungi . 7 Marine Environments. 8 Plants. 9 Testing Compounds . 11 Existing Antibiotics . 14 Genomics . 19 Combinatorial Chemistry. 22 Bringing a Drug to Market . 25 Preclinical Trials . 25 Animal Safety Studies . 26 Clinical Trials . 27 Future of Antimicrobial Development . 28 II. MATERIALS AND METHODS . 31 Source of Compounds to be Tested . 31 Bacterial and Fungal Isolates . 35 Inoculation of Media . 35 iv Inoculum Size. 36 Incubation Time . 38 Dimethyl Sulfoxide (DMSO) for Putting Compounds into Solution . 38 Volume of Liquid to Place on Filter Paper Disks . 40 Evaluation of Testing Interference Due to Resin Beads . 41 Evaluation of the Newly Developed Test System . 42 Media . 43 Testing Compounds . 46 Effects of DMSO and Resin Beads on a Cell Culture System . 47 Determination of Best Diluent for Cytotoxicity Experiments . 49 Testing Compounds for Toxicity . 52 III. RESULTS . 53 Activity of Chemical Compounds . 53 Replicate Testing . 57 Toxicity Studies . 59 IV. DISCUSSION . 62 Chemical Compounds . 62 Test System for Biological Activity . 63 Toxicity Testing . 65 Biological Activity of Compounds . 66 Limiting Factor . 68 Conclusion . 69 V. REFERENCES . 70 v LIST OF FIGURES Figure Page 1. Percent resistance in selected antibiotics in Staphylococcus aureus . 2 2. Percent resistance in selected antibiotics in Acinetobacter baumanii . 2 3. Chemical structures of Cephamycin C and Cefoxitin . 17 4. Structure of aztreonam . 18 5. Basic structure of a quinolone . 19 6. Solid-phase synthesis . 22 7. Liquid-phase synthesis . 23 8. Split synthesis protocol . 24 9. Diagrammatic representation of plate inoculation . 36 10. Turbidity meter . 37 11. RPMI 1640 and Mueller Hinton agars demonstrating zones of inhibition 47 12. Rotating drug for cell culture tubes . 49 13. Effects of agar thickness when testing compounds . 59 14. Toxicity sees on MRC-5 cells used in toxicity studies . 61 15. Structure of Mefloquine . 62 16. Structures of hydantoins, amides, and sulfonamides . 63 vi LIST OF TABLES Table Page 1. Name and number of chemical compounds used . 31 2. Zones of inhibition for DMSO dilutions . 40 3. Crystal violet volume required to saturate disk . 41 4. Zones of inhibition for resin beads . 42 5. Zones of inhibition for antimicrobial control compounds . 43 6. Zones of inhibition for media formulations . 46 7. Cytotoxicity of DMSO and resin beads . 49 8. Cytotoxicity of DMSO dilutions and ethanol . 50 9. Water as a possible diluent for two compounds . 51 10. Toxicity of DMSO at high dilutions . 51 11. Zones of inhibition for each compound . 53 12. Names and chemical structures of biologically active compounds . 55 13. Zones of inhibition caused by dilutions of octylamine . 56 14. Replicate testing of biologically active compounds . 57 15. Toxicity of compounds that are biologically active . 60 16. Antimicrobial Activity of Benzamides, Sulfonamides, and . 67 Benzenesulfonamides 17. Activity of Benzamides, Sulfonamides, and Benzenesulfonamides . 68 in mammalian cells Appendix Table A1. Supplies . 79 vii INTRODUCTION Importance of Finding New Antimicrobials The use of antimicrobial agents is critical to successful treatment of infectious diseases. Although there are numerous classes of drugs that are routinely used to treat infections in humans, there are several reasons why the discovery and development of new antimicrobial agents are important. Over the past decade there has been an increased development of resistance in organisms that are typical pathogens in humans. These include methicillin/oxacillin-resistant Staphylococcus aureus (1,2), vancomycin- resistant and intermediate Staphylococcus aureus (3,4), vancomycin-resistant Enterococcus (2,5), gram-neagtive bacilli that produce extended spectrum beta- lactamases (6,7), carbapenem-resistant Klebsiella pneumoniae (8), and Pseudomonas and Acinetobacter (9) strains that are resistant to all antibiotics that are typically used for treatment. Figures 1 and 2 show a graphical representation of the rise in resistance for two common pathogenic organisms that are isolated in clinical laboratories (10). This increased resistance has limited the selection of antimicrobials that may be used to treat specific organisms. 1 Pe rce nt Re sista nce in Staphylococcus aureus 1996-2006 80 70 60 50 Oxacillin 40 30 Erythromycin 20 10 0 96 9 002 004 006 1 1998 2000 2 2 2 Figure 1: Percent resistance in selected antibiotics in Staphylococcus aureus at CompuNet Clinical Lab, Moraine, Ohio, 1996 to 2006 (10). Pe rce nt Re sista nce in Acinetobacter baumanii 1996-2006 100 80 Amikacin 60 Cef taz idime 40 Ciprofloxacin 20 0 0 4 0 0 0 0 1996 1998 2 2002 2 2006 Figure 2: Percent resistance in selected antibiotics in Acinetobacter baumanii at CompuNet Clinical Lab, Moraine, Ohio, 1996 to 2006 (10). New antimicrobials are also needed for certain groups of organisms. Very limited numbers of antimicrobials are available to treat infections caused by fungi and 2 mycobacteria. Infections with these organisms continue to be a major concern. Chemotherapy for cancer treatment, immunosuppressive drugs for treatment of autoimmune diseases and organ transplant recipients, and infections (such as AIDS) that alter the effectiveness of the host immune system render individuals at high risk for fungal infections and certain mycobacterial infections. Often these infections are caused by environmental organisms that would not typically cause disease in a normal host. There are increased numbers of reports of multi-drug resistant mycobacteria in the United States and throughout the world (11). Another complicating factor that reduces the effectiveness of treatment of these organisms is non-compliance in completing treatment regimens. Extended length of treatment (sometimes up to one year) and adverse side effects of the drugs used
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