Discovery of Novel Natural Products to Combat Multidrug Resistant Bacteria and Fungi Restricted; Files Only
Marquez, Lewis (Fall 2023)
Published
Abstract
Antimicrobial resistance (AMR) is one of the world’s most urgent impending threats. There are estimates that AMR infections will account for 10 million deaths a year globally by 2050. Reports attribute 35,000 deaths a year in the United States to AMR infections. Despite these threats, there has been a disinvestment in antibiotic and antifungal drug discovery research. This leaves a critical need for the research and development of new antimicrobial drugs.
To address this need, we propose chemically mining the natural world. Plants have historically been the fundamental source of medicines for treating human diseases. Ethnobotany, or the study of the traditional uses of plants as medicines, has a rich history in drug discovery. Plants used in traditional medicine are valuable sources of chemically diverse antimicrobial compounds. In this dissertation, I provide researchers with information from the literature on plant species with antimicrobial activity to strategically select the best candidates to chemically mine for new antimicrobial compounds. I also highlighted the most promising plant natural products for future optimization studies.
Synergistic compounds are another method through which AMR can be addressed. From an extract of Callicarpa americana, we isolated and derivatized the clerodane diterpene compound 12(S),16ξ-dihydroxycleroda-3,13-dien-15,16-olide, which we found resensitized methicillin-resistant Staphylococcus aureus to the ß-Lactam class of antibiotics. We also identified key structural components necessary for the synergistic activity of the clerodane diterpene compound.
In this dissertation, I also report on the potent antimicrobial activity of penta-O-galloyl-β-D-glucose (PGG). We found that PGG displayed antibacterial activity against carbapenem-resistant Acinetobacter baumannii and potent antifungal activity against multiple Candida species. Additionally, we sought to elucidate the mechanism of action for the antifungal activity of PGG. We found that PGG acts as a strong iron chelator and that loss of key iron homeostasis genes in Candida albicans led to hypersensitivity to PGG.
Together, this work presents the utility of plant natural products as the basis for new therapeutics to treat drug-resistant microbial infections as well as my contributions to new technologies in the field of natural product science. Moreover, this dissertation emphasizes the value of plant natural products in antibiotic drug discovery.
Table of Contents
CHAPTER 1: INTRODUCTION 1
CHAPTER 1.1: ANTIMICROBIAL RESISTANCE 1
CHAPTER 1.2: NATURAL PRODUCTS AS MEDICINE 3
CHAPTER 1.3: SUMMARY SECTION 5
CHAPTER 2: A REVIEW OF THE FIELD OF NATURAL PRODUCTS TO COMBAT DRUG RESISTANT MICROBES 8
CHAPTER 2.1: A SYSTEMATIC REVIEW OF PLANTS WITH ANTIBACTERIAL ACTIVITIES: A TAXONOMIC AND PHYLOGENETIC PERSPECTIVE 14
CHAPTER 2.2: ETHNOBOTANY AND THE ROLE OF PLANT NATURAL PRODUCTS IN ANTIBIOTIC DRUG DISCOVERY 78
CHAPTER 2.3: RECENT ADVANCES IN THE DISCOVERY OF PLANT-DERIVED ANTIMICROBIAL NATURAL PRODUCTS TO COMBAT ANTIMICROBIAL RESISTANT PATHOGENS: INSIGHTS FROM 2018–2022 232
CHAPTER 2.4: PREVALENCE AND THERAPEUTIC CHALLENGES OF FUNGAL DRUG RESISTANCE: ROLE FOR PLANTS IN DRUG DISCOVERY 282
CHAPTER 3: ADJUVANTS AND SYNERGISTIC NATURAL PRODUCTS 295
CHAPTER 3.1: QUANTIFYING SYNERGY IN THE BIOASSAY-GUIDED FRACTIONATION OF NATURAL SUBSTANCES 299
CHAPTER 3.2: A CLERODANE DITERPENE FROM CALLICARPA AMERICANA RESENSITIZES METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS TO ß-LACTAM ANTIBIOTICS 320
CHAPTER 3.3: SYNTHESIS, STEREOCHEMICAL CONFIRMATION, AND DERIVATIZATION OF 12(S),16ϵ-DIHYDROXYCLERODA-3,13-DIEN-15,16-OLIDE, A CLERODANE DITERPENE THAT SENSITIZES METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS TO Β-LACTAM ANTIBIOTICS 349
CHAPTER 4: NATURAL PRODUCTS TO COMBAT DRUG-RESISTANT BACTERIA 363
CHAPTER 4.1: PENTAGALLOYL GLUCOSE FROM SCHINUS TEREBINTHIFOLIA INHIBITS GROWTH OF CARBAPENEM-RESISTANT ACINETOBACTER BAUMANNII 366
CHAPTER 4.2: CRYPTIC CHEMICAL VARIATION IN A MARINE RED ALGA AS REVEALED BY NONTARGETED METABOLOMICS 410
CHAPTER 5: NATURAL PRODUCTS TO COMBAT DRUG RESISTANT FUNGI 441
CHAPTER 5.1: POTENT ANTIFUNGAL ACTIVITY OF PENTA-O-GALLOYL-Β-D-GLUCOSE AGAINST DRUG-RESISTANT CANDIDA ALBICANS, CANDIDA AURIS, AND OTHER NON-ALBICANS CANDIDA SPECIES 445
CHAPTER 5.2: ANTIFUNGAL ACTIVITY OF LECHEA MUCRONATA EXTRACTS 491
CHAPTER 6: NEW AND EMERGING TECHNOLOGIES 501
CHAPTER 6.1: CUSTOMIZABLE LARGE-SCALE HPLC FRACTION COLLECTION USING LOW-COST 3D PRINTING 504
CHAPTER 6.2: HIGH-THROUGHPUT IDENTIFICATION OF CRYSTALLINE NATURAL PRODUCTS FROM CRUDE EXTRACTS ENABLED BY MICROARRAY TECHNOLOGY AND MICROED 515
CHAPTER 7: DISCUSSION AND FUTURE DIRECTIONS 532
BIBLIOGRAPHY 538
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File download under embargo until 10 January 2030 | 2023-12-13 18:22:11 -0500 | File download under embargo until 10 January 2030 |
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