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The discovery and development of novel antibacterial agents is essential to address the rising health concern over antibiotic resistant bacteria. This research investigated the antibacterial activity of a natural clay deposit near Crater Lake, Oregon, that is effective at killing antibiotic resistant human pathogens. The primary rock types in the deposit are andesitic pyroclastic materials, which have been hydrothermally altered into argillic clay zones. High-sulfidation (acidic) alteration produced clay zones with elevated pyrite (18%), illite-smectite (I-S) (70% illite), elemental sulfur, kaolinite and carbonates. Low-sulfidation alteration at neutral pH generated clay zones with lower pyrite concentrations pyrite (4-6%), the mixed-layered I-S clay rectorite (R1, I-S) and quartz.
Antibacterial susceptibility testing reveals that hydrated clays containing pyrite and I-S are effective at killing (100%) of the model pathogens tested (E. coli and S. epidermidis) when pH (< 4.2) and Eh (> 450 mV) promote pyrite oxidation and mineral dissolution, releasing > 1 mM concentrations of Fe2+, Fe3+ and Al3+. However, certain oxidized clay zones containing no pyrite still inhibited bacterial growth. These clays buffered solutions to low pH (< 4.7) and oxidizing Eh (> 400 mV) conditions, releasing lower amounts (< 1 mM) of Fe and Al. The presence of carbonate in the clays eliminated antibacterial activity due to increases in pH, which lower pyrite oxidation and mineral dissolution rates.
The antibacterial mechanism of these natural clays was explored using metal toxicity and genetic assays, along with advanced bioimaging techniques. Antibacterial clays provide a continuous reservoir of Fe2+, Fe3+ and Al3+ that synergistically attack pathogens while generating hydrogen peroxide (H2O¬2). Results show that dissolved Fe2+ and Al3+ are adsorbed to bacterial envelopes, causing protein misfolding and oxidation in the outer membrane. Only Fe2+ is taken up by the cells, generating oxidative stress that damages DNA and proteins. Excess Fe2+ oxidizes inside the cell and precipitates Fe3+-oxides, marking the sites of hydroxyl radical (•OH) generation. Recognition of this novel geochemical antibacterial process should inform designs of new mineral based antibacterial agents and could provide a new economic industry for such clays.
Antibacterial susceptibility testing reveals that hydrated clays containing pyrite and I-S are effective at killing (100%) of the model pathogens tested (E. coli and S. epidermidis) when pH (< 4.2) and Eh (> 450 mV) promote pyrite oxidation and mineral dissolution, releasing > 1 mM concentrations of Fe2+, Fe3+ and Al3+. However, certain oxidized clay zones containing no pyrite still inhibited bacterial growth. These clays buffered solutions to low pH (< 4.7) and oxidizing Eh (> 400 mV) conditions, releasing lower amounts (< 1 mM) of Fe and Al. The presence of carbonate in the clays eliminated antibacterial activity due to increases in pH, which lower pyrite oxidation and mineral dissolution rates.
The antibacterial mechanism of these natural clays was explored using metal toxicity and genetic assays, along with advanced bioimaging techniques. Antibacterial clays provide a continuous reservoir of Fe2+, Fe3+ and Al3+ that synergistically attack pathogens while generating hydrogen peroxide (H2O¬2). Results show that dissolved Fe2+ and Al3+ are adsorbed to bacterial envelopes, causing protein misfolding and oxidation in the outer membrane. Only Fe2+ is taken up by the cells, generating oxidative stress that damages DNA and proteins. Excess Fe2+ oxidizes inside the cell and precipitates Fe3+-oxides, marking the sites of hydroxyl radical (•OH) generation. Recognition of this novel geochemical antibacterial process should inform designs of new mineral based antibacterial agents and could provide a new economic industry for such clays.
ContributorsMorrison, Keith D (Author) / Williams, Lynda B (Thesis advisor) / Williams, Stanley N (Thesis advisor) / Misra, Rajeev (Committee member) / Shock, Everett (Committee member) / Anbar, Ariel (Committee member) / Arizona State University (Publisher)
Created2015
Description
Leprosy and tuberculosis are age-old diseases that have tormented mankind and left behind a legacy of fear, mutilation, and social stigmatization. Today, leprosy is considered a Neglected Tropical Disease due to its high prevalence in developing countries, while tuberculosis is highly endemic in developing countries and rapidly re-emerging in several developed countries. In order to eradicate these diseases effectively, it is necessary to understand how they first originated in humans and whether they are prevalent in nonhuman hosts which can serve as a source of zoonotic transmission. This dissertation uses a phylogenomics approach to elucidate the evolutionary histories of the pathogens that cause leprosy and tuberculosis, Mycobacterium leprae and the M. tuberculosis complex, respectively, through three related studies. In the first study, genomes of M. leprae strains that infect nonhuman primates were sequenced and compared to human M. leprae strains to determine their genetic relationships. This study assesses whether nonhuman primates serve as a reservoir for M. leprae and whether there is potential for transmission of M. leprae between humans and nonhuman primates. In the second study, the genome of M. lepraemurium (which causes leprosy in mice, rats, and cats) was sequenced to clarify its genetic relationship to M. leprae and other mycobacterial species. This study is the first to sequence the M. lepraemurium genome and also describes genes that may be important for virulence in this pathogen. In the third study, an ancient DNA approach was used to recover M. tuberculosis genomes from human skeletal remains from the North American archaeological record. This study informs us about the types of M. tuberculosis strains present in post-contact era North America. Overall, this dissertation informs us about the evolutionary histories of these pathogens and their prevalence in nonhuman hosts, which is not only important in an anthropological context but also has significant implications for disease eradication and wildlife conservation.
ContributorsHonap, Tanvi Prasad (Author) / Stone, Anne C (Thesis advisor) / Rosenberg, Michael S. (Thesis advisor) / Clark-Curtiss, Josephine E (Committee member) / Krause, Johannes (Committee member) / Arizona State University (Publisher)
Created2017