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Eradication of multidrug-resistant bacteria using biomolecule-encapsulated two-dimensional materials
Description
The increasing pervasiveness of infections caused by multidrug-resistant bacteria (MDR) is a major global health issue that has been further exacerbated by the dearth of antibiotics developed over the past 40 years. Drug-resistant bacteria have led to significant morbidity and mortality, and ever-increasing antibiotic resistance threatens to reverse many of the medical advances enabled by antibiotics over the last 40 years. The traditional strategy for combating these superbugs involves the development of new antibiotics. Yet, only two new classes of antibiotics have been introduced to the clinic over the past two decades, and both failed to combat broad spectrum gram-negative bacteria. This situation demands alternative strategies to combat drug-resistant superbugs. Herein, these dissertation reports the development of potent antibacterials based on biomolecule-encapsulated two-dimensional inorganic materials, which combat multidrug-resistant bacteria using alternative mechanisms of strong physical interactions with bacterial cell membrane. These systems successfully eliminate all members of the ‘Superbugs’ set of pathogenic bacteria, which are known for developing antibiotic resistance, providing an alternative to the limited ‘one bug-one drug’ approach that is conventionally used. Furthermore, these systems demonstrate a multimodal antibacterial killing mechanism that induces outer membrane destabilization, unregulated ion movement across the membranes, induction of oxidative stress, and finally apoptotic-like cell death. In addition, a peptide-encapsulation of the two-dimensional material successfully eliminated biofilms and persisters at micromolar concentrations. Overall, these novel systems have great potential as next-generation antimicrobial agents for eradication of broad spectrum multidrug-resistant bacteria.
ContributorsDebnath, Abhishek (Author) / Green, Alexander A (Thesis advisor) / Liu, Yan (Committee member) / Stephanopoulos, Nicholas (Committee member) / Arizona State University (Publisher)
Created2019
Description
Chemical modification of (semi)conducting surfaces with soft-material coatings containing electrocatalysts provides a strategy for developing integrated constructs that capture, convert, and store solar energy as fuels. However, a lack of effective strategies for interfacing electrocatalysts with solid-state materials, and an incomplete understanding of performance limiting factors, inhibit further development. In this work, chemical modification of a nanostructured transparent conductive oxide, and the III-V semiconductor, gallium phosphide, is achieved by applying a thin-film polymer coating containing appropriate functional groups to direct, template, and assemble molecular cobalt catalysts for activating fuel-forming reactions. The heterogeneous-homogeneous conducting assemblies enable comparisons of the structural and electrochemical properties of these materials with their homogeneous electrocatalytic counterparts. For these hybrid constructs, rational design of the local soft-material environment yields a nearly one-volt span in the redox chemistry of the cobalt metal centers. Further, assessment of the interplay between light absorption, charge transfer, and catalytic activity in studies involving molecular-catalyst-modified semiconductors affords models to describe the rates of photoelectrosynthetic fuel production as a function of the steady-state concentration of catalysts present in their activated form. These models provide a conceptual framework for extracting kinetic and thermodynamic benchmarking parameters. Finally, investigation of molecular ‘proton wires’ inspired by the Tyrosine Z-Histidine 190 redox pair in Photosystem II, provides insight into fundamental principles governing proton-coupled electron transfer, a process essential to all fuel-forming reactions relevant to solar fuel generation.
ContributorsWadsworth, Brian Lawrence (Author) / Moore, Gary F (Thesis advisor) / Moore, Thomas A. (Committee member) / Trovitch, Ryan J (Committee member) / Arizona State University (Publisher)
Created2020
Description
Global industrialization and urbanization have led to increased levels of air pollution. The costs to society have come in the form of environmental damage, healthcare expenses, lost productivity, and premature mortality. Measuring pollutants is an important task for identifying its sources, warning individuals about dangerous exposure levels, and providing epidemiologists with data to link pollutants with diseases. Current methods for monitoring air pollution are inadequate though. They rely on expensive, complex instrumentation at limited fixed monitoring sites that do not capture the true spatial and temporal variation. Furthermore, the fixed outdoor monitoring sites cannot warn individuals about indoor air quality or exposure to chemicals at worksites. Recent advances in manufacturing and computing technology have allowed new classes of low-cost miniature gas sensor to emerge as possible alternatives. For these to be successful however, there must be innovations in the sensors themselves that improve reliability, operation, and their stability and selectivity in real environments. Three novel gas sensor solutions are presented. The first is the development of a wearable personal exposure monitor using all commercially available components, including two metal oxide semiconductor gas sensors. The device monitors known asthma triggers: ozone, total volatile organic compounds, temperature, humidity, and activity level. Primary focus is placed on the ozone sensor, which requires special circuits, heating algorithm, and calibration to remove temperature and humidity interferences. Eight devices are tested in multiple field tests. The second is the creation of a new compact optoelectronic gas sensing platform using colorimetric microdroplets printed on the surface of a complementary-metal-oxide-semiconductor (CMOS) imager. The nonvolatile liquid microdroplets provide a homogeneous, uniform environment that is ideal for colorimetric reactions and lensless optical measurements. To demonstrate one type of possible indicating system gaseous ammonia is detected by complexation with Cu(II). The third project continues work on the CMOS imager optoelectronic platform and develops a more robust sensing system utilizing hydrophobic aerogel particles. Ammonia is detected colorimetrically by its reaction with a molecular dye, with additives and surface treatments enhancing uniformity of the printed films. Future work presented at the end describes a new biological particle sensing system using the CMOS imager.
ContributorsMallires, Kyle Reed (Author) / Tao, Nongjian (Thesis advisor) / Forzani, Erica (Thesis advisor) / Wiktor, Peter (Committee member) / Wang, Di (Committee member) / Alford, Terry (Committee member) / Xian, Xiaojun (Committee member) / Arizona State University (Publisher)
Created2020
Description
Coronaviruses are the causative agents of SARS, MERS and the ongoing COVID-19 pandemic. Coronavirus envelope proteins have received increasing attention as drug targets, due to their multiple functional roles during the infection cycle. The murine coronavirus mouse hepatitis virus strain A59, a hepatic and neuronal tropic coronavirus, is considered a prototype of the betacoronaviruses. The envelope protein of the mouse hepatitis virus (MHV-E) was extensively screened with various membrane mimetics by solution state nuclear magnetic resonance spectroscopy to find a suitable mimetic, which allowed for assignment of ~97% of the backbone atoms in the transmembrane region. Following resonance assignments, the binding site of the ion channel inhibitor hexamethylene amiloride (HMA) was mapped to MHV-E using chemical shift perturbations in both amide and aromatic transverse relaxation optimized spectroscopy (TROSY) spectra, which indicated the inhibitor binding site is located at the N-terminal opening of the channel, in accord with one of the proposed HMA binding sites in the envelope protein from the related SARS (severe acute respiratory syndrome) betacoronavirus. Structure calculation of residues M1-K38 of MHV-E, encompassing the transmembrane region, is currently in progress using dihedral angle restraints obtained from isotropic chemical shifts and distance restraints obtained from manually assigned NOE cross-peaks, with the ultimate aim of generating a model of the MHV-E viroporin bound to the inhibitor HMA. This work outlines the first NMR studies on MHV-E, which have provided a foundation for structure based drug design and probing interactions, and the methods can be extended, with suitable modifications, to other coronavirus envelope proteins.
ContributorsBaravati, Bobby (Author) / Fromme, Petra (Thesis advisor) / Hansen, Debra (Thesis advisor) / Van Horn, Wade (Committee member) / Wang, Xu (Committee member) / Arizona State University (Publisher)
Created2020
Description
Oxidoreductases catalyze transformations important in both bioenergetics and microbial technologies. Nonetheless, questions remain about how to tune them to modulate properties such as preference for catalysis in the oxidative or reductive direction, the potential range of activity, or coupling of multiple reactions. Using protein film electrochemistry, the features that control these properties are defined by comparing the activities of five [FeFe]-hydrogenases and two thiosulfate reductases. Although [FeFe]-hydrogenases are largely described as hydrogen evolution catalysts, the catalytic bias of [FeFe]-hydrogenases, i.e. the ratio of maximal reductive to oxidative activities, spans more than six orders of magnitude. At one extreme, two [FeFe]-hdyrogenases, Clostridium pasteuriaunum HydAII and Clostridium symbiosum HydY, are far more active for hydrogen oxidation than hydrogen evolution. On the other extreme, Clostridium pasteurianum HydAI and Clostridium acetobutylicum HydA1 have a neutral bias, in which both proton reduction and hydrogen oxidation are efficient. By investigating a collection of site-directed mutants, it is shown that the catalytic bias of [FeFe]-hydrogenases is not trivially correlated with the identities of residues in the primary or secondary coordination sphere. On the other hand, the catalytic bias of Clostridium acetobutylicum HydAI can be modulated via mutation of an amino acid residue coordinating the terminal [FeS] cluster. Simulations suggest that this change in catalytic bias may be linked to the reduction potential of the cluster.
Two of the enzymes examined in this work, Clostridium pasteurianum HydAIII and Clostridium symbiosum HydY, display novel catalytic properties. HydY is exclusively a hydrogen oxidizing catalyst, and it couples this activity to peroxide reduction activity at a rubrerythrin center in the same enzyme. On the other hand, CpIII operates only in a narrow potential window, inactivating at oxidizing potentials. This suggests it plays a novel physiological role that has not yet been identified. Finally, the electrocatalytic properties of Pyrobaculum aerophilum thiosulfate reductase with either Mo or W in the active site are compared. In both cases, the onset of catalysis corresponds to reduction of the active site. Overall, the Mo enzyme is more active, and reduces thiosulfate with less overpotential.
Two of the enzymes examined in this work, Clostridium pasteurianum HydAIII and Clostridium symbiosum HydY, display novel catalytic properties. HydY is exclusively a hydrogen oxidizing catalyst, and it couples this activity to peroxide reduction activity at a rubrerythrin center in the same enzyme. On the other hand, CpIII operates only in a narrow potential window, inactivating at oxidizing potentials. This suggests it plays a novel physiological role that has not yet been identified. Finally, the electrocatalytic properties of Pyrobaculum aerophilum thiosulfate reductase with either Mo or W in the active site are compared. In both cases, the onset of catalysis corresponds to reduction of the active site. Overall, the Mo enzyme is more active, and reduces thiosulfate with less overpotential.
ContributorsWilliams, Samuel Garrett (Author) / Jones, Anne K (Thesis advisor) / Hayes, Mark A. (Committee member) / Trovitch, Ryan J (Committee member) / Arizona State University (Publisher)
Created2020
Description
Organic compounds are influenced by hydrothermal conditions in both marine and terrestrial environments. Sedimentary organic reservoirs make up the largest share of organic carbon in the carbon cycle, leading to petroleum generation and to chemoautotrophic microbial communities. There have been numerous studies on the reactivity of organic compounds in water at elevated temperatures, but these studies rarely explore the consequences of inorganic solutes in hydrothermal fluids. The experiments in this thesis explore new reaction pathways of organic compounds mediated by aqueous and solid phase metals, mainly Earth-abundant copper. These experiments show that copper species have the potential to oxidize benzene and toluene, which are typically viewed as unreactive. These pathways add to the growing list of known organic transformations that are possible in natural hydrothermal systems. In addition to the characterization of reactions in natural systems, there has been recent interest in using hydrothermal conditions to facilitate organic transformations that would be useful in an applied, industrial or synthetic setting. This thesis identifies two sets of conditions that may serve as alternatives to commonplace industrial processes. The first process is the oxidation of benzene with copper to form phenol and chlorobenzene. The second is the copper mediated dehalogenation of aryl halides. Both of these processes apply the concepts of geomimicry by carrying out organic reactions under Earth-like conditions. Only water and copper are needed to implement these processes and there is no need for exotic catalysts or toxic reagents.
ContributorsLoescher, Grant (Author) / Shock, Everett (Thesis advisor) / Hartnett, Hilairy (Committee member) / Gould, Ian (Committee member) / Arizona State University (Publisher)
Created2020
Description
Mixed-ionic electronic conducting (MIEC) oxides have drawn much attention from researchers because of their potential in high temperature separation processes. Among many materials available, perovskite type and fluorite type oxides are the most studied for their excellent oxygen ion transport property. These oxides not only can be oxygen adsorbent or O2-permeable membranes themselves, but also can be incorporated with molten carbonate to form dual-phase membranes for CO2 separation.
Oxygen sorption/desorption properties of perovskite oxides with and without oxygen vacancy were investigated first by thermogravimetric analysis (TGA) and fixed-bed experiments. The oxide with unique disorder-order phase transition during desorption exhibited an enhanced oxygen desorption rate during the TGA measurement but not in fixed-bed demonstrations. The difference in oxygen desorption rate is due to much higher oxygen partial pressure surrounding the sorbent during the fixed-bed oxygen desorption process, as revealed by X-ray diffraction (XRD) patterns of rapidly quenched samples.
Research on using perovskite oxides as CO2-permeable dual-phase membranes was subsequently conducted. Two CO2-resistant MIEC perovskite ceramics, Pr0.6Sr0.4Co0.2Fe0.8 O3-δ (PSCF) and SrFe0.9Ta0.1O3-δ (SFT) were chosen as support materials for membrane synthesis. PSCF-molten carbonate (MC) and SFT-MC membranes were prepared for CO2-O2 counter-permeation. The geometric factors for the carbonate phase and ceramic phase were used to calculate the effective carbonate and oxygen ionic conductivity in the carbonate and ceramic phase. When tested in CO2-O2 counter-permeation set-up, CO2 flux showed negligible change, but O2 flux decreased by 10-32% compared with single-component permeation. With CO2 counter-permeation, the total oxygen permeation flux is higher than that without counter-permeation.
A new concept of CO2-permselective membrane reactor for hydrogen production via steam reforming of methane (SRM) was demonstrated. The results of SRM in the membrane reactor confirm that in-situ CO2 removal effectively promotes water-gas shift conversion and thus enhances hydrogen yield. A modeling study was also conducted to assess the performance of the membrane reactor in high-pressure feed/vacuum sweep conditions, which were not carried out due to limitations in current membrane testing set-up. When 5 atm feed pressure and 10-3 atm sweep pressure were applied, the membrane reactor can produce over 99% hydrogen stream in simulation.
Oxygen sorption/desorption properties of perovskite oxides with and without oxygen vacancy were investigated first by thermogravimetric analysis (TGA) and fixed-bed experiments. The oxide with unique disorder-order phase transition during desorption exhibited an enhanced oxygen desorption rate during the TGA measurement but not in fixed-bed demonstrations. The difference in oxygen desorption rate is due to much higher oxygen partial pressure surrounding the sorbent during the fixed-bed oxygen desorption process, as revealed by X-ray diffraction (XRD) patterns of rapidly quenched samples.
Research on using perovskite oxides as CO2-permeable dual-phase membranes was subsequently conducted. Two CO2-resistant MIEC perovskite ceramics, Pr0.6Sr0.4Co0.2Fe0.8 O3-δ (PSCF) and SrFe0.9Ta0.1O3-δ (SFT) were chosen as support materials for membrane synthesis. PSCF-molten carbonate (MC) and SFT-MC membranes were prepared for CO2-O2 counter-permeation. The geometric factors for the carbonate phase and ceramic phase were used to calculate the effective carbonate and oxygen ionic conductivity in the carbonate and ceramic phase. When tested in CO2-O2 counter-permeation set-up, CO2 flux showed negligible change, but O2 flux decreased by 10-32% compared with single-component permeation. With CO2 counter-permeation, the total oxygen permeation flux is higher than that without counter-permeation.
A new concept of CO2-permselective membrane reactor for hydrogen production via steam reforming of methane (SRM) was demonstrated. The results of SRM in the membrane reactor confirm that in-situ CO2 removal effectively promotes water-gas shift conversion and thus enhances hydrogen yield. A modeling study was also conducted to assess the performance of the membrane reactor in high-pressure feed/vacuum sweep conditions, which were not carried out due to limitations in current membrane testing set-up. When 5 atm feed pressure and 10-3 atm sweep pressure were applied, the membrane reactor can produce over 99% hydrogen stream in simulation.
ContributorsWu, Han-Chun (Author) / Lin, Jerry Y.S. (Thesis advisor) / Deng, Shuguang (Committee member) / Jiao, Yang (Committee member) / Emady, Heather (Committee member) / Muhich, Christopherq (Committee member) / Arizona State University (Publisher)
Created2020
Description
This dissertation focuses on the structure-function relationships of nanomaterials (NMs) and some of their applications in environmental engineering. The aim is to investigate NMs of different surface chemistries and assess their interactions with biological models, evaluate the weathering impact and degradation parameters to improve polymer coatings, test their efficiency for contaminant removal and provide further understanding in the safe design of nanomaterials. Nanoecotoxicological risk assessment currently suffers from a lack of testing procedures adapted to nanomaterials. Graphene oxide (GO) is a carbon nanomaterial (CNM) that consists of a single layer of carbon atoms arranged in a hexagonal network. It is decorated with a high density of oxygen functional groups including epoxide and hydroxyl moieties on the basal planes and carboxylic and carbonyl groups at the edges. The changes in surface chemistry give GO unique properties that can be tailored for a function. Additionally, because of its simple synthesis and flexible chemistry, GO has been a popular building block of many composite CNMs. In environmental engineering, specifically, water treatment, GO has been studied by itself or as a composite for pollutant removal, biofouling reduction, and as an antimicrobial agent, just to name a few. Like GO, silver (Ag) is another NM widely used in water treatment for its biocidal properties. Despite the recent growth in this field, a fundamental understanding of the function-structure relationships in NMs is still progressing. Through a systematic set of experiments, the structure-properties-function and structure-properties-hazard relationships were investigated. These relationships can be used to establish guidelines to engineer “safe-by-design” functional nanomaterials, where materials are tailored to enhance their function while minimizing their inherent biological or environmental hazard.
ContributorsBarrios, Ana Cecilia (Author) / Perreault, Francois (Thesis advisor) / Abbaszadegan, Morteza (Committee member) / Conroy-Ben, Otakuye (Committee member) / Hua-Wang, Qing (Committee member) / Arizona State University (Publisher)
Created2021
Description
Since the inception of DNA nanotechnology, DNA has found itself poised as one of the most robust self-assembling building blocks due to its well understood double helix structure formed by two anti-parallel strands of DNA held together by hydrogen bond from nucleobases which also provides the material programmability due to the well-understood Watson Crick base pairing rules. These capabilities have led to the exponential increase in publications showing off intricate and remarkable designs alongside ever-expanding applications. However, as the field expands there is an apparent lack of chemical diversity and functionality. To combat this my research focused on creating hybrid peptide oligonucleotide conjugates (POC) where the conjugated peptide could add chemical and structural diversity using the 20 canonical amino acids and various peptide secondary structures. In this work, I conjugate DNA to the self-assembling peptide building block the coiled coil. The coiled coil motif is formed from the self-assembly of two or more α-helical peptides and, like DNA, the coiled coil has well understood programmability. Together as a conjugate, the DNA and coiled coil, create a new self-assembling building block capable of two orthogonal self-assembling modes that can work in tandem. In this work, I used DNA coiled coil conjugates to show the capability to create first of their kind hybrid DNA/coiled coil one-dimensional fibers (chapter 2), integrate proteins (chapter 3), and to create hybrid cage structures (chapter 4). Finally, a POC hydrogel is created using the polypeptide gelatin with DNA crosslinks to create a reversible stiffening gel using toe-hold mediated strand displacement (chapter 5).
ContributorsBuchberger, Alex Richard (Author) / Stephanopoulos, Nicholas (Thesis advisor) / Mills, Jeremy (Committee member) / Van Horn, Wade (Committee member) / Arizona State University (Publisher)
Created2021
Description
Fluorescence spectroscopy has been a vital technique in biophysics due to its high sensitivity and specificity. While the recent development of single-molecule (SM) techniques has furthered the molecular-level understanding of complicated biological systems, the full potential of these techniques hinges on the development and selection of fluorescent probes with customized photophysical properties. Red region probes are inherently desirable as background noise from typical biological systems tends to be at its minimum in this spectral region. The first part of this work studies the photophysical properties of red cyanine dyes to access their usefulness for particular SM applications.Protein-induced fluorescence enhancement (PIFE) based approaches are increasingly being used to investigate DNA-protein interactions at the SM level. However, a key limitation remains the absence of good red PIFE probes. This work investigates the photophysical properties of a red hemicyanine dye (Dy-630) as a potential PIFE probe. Results shed light on optimal design principles for ideal probes for PIFE applications, opening new avenues for the technique’s broad applicability in biophysical studies.
Further, the photophysical behavior of two novel cyanine fluorophores in the far-red (rigidized pentacyanine) and near-Infrared (IR) (rigidized heptacyanine) region are studied. Both probes are designed to eliminate a photoisomerization caused non-radiative pathway by rigidization of the cyanine backbone. The rigidized pentacyanine was found to have desired photophysical properties and improved quantum yield, vital for application in super-resolution imaging. For rigidized heptacyanine, in contrast to the prior project, it was found that photoisomerization does not contribute significantly to the deactivation pathway. Thus, this work clarifies the role of photoisomerization on heptamethine cyanine scaffold and will enable future efforts to optimize NIR dyes for diverse applications.
The second part of this work aims to answer the fundamental question of how the physics of DNA can impact its biology. To this end, interlinkage between the flexibility of local sequence context and the efficiency of uracil removal by Uracil-DNA glycosylase (UDG) protein is investigated using fluorescent base analogue, 2-Aminopurine (2-AP).
In summary, this work focuses on photophysical investigations, the understanding of which is vital for the selection and development of fluorescent probes for biophysical studies.
ContributorsKumari, Nikita (Author) / Levitus, Marcia (Thesis advisor) / Gould, Ian (Committee member) / Liu, Yan (Committee member) / Arizona State University (Publisher)
Created2021