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You searched for +publisher:"Vanderbilt University" +contributor:("John A. McLean, Ph.D."). Showing records 1 – 2 of 2 total matches.

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Vanderbilt University

1. Lockhart, Jacob Nathaniel. Synthesis of Nanomaterials and Macromolecular Architectures for Dual Drug Delivery Systems, Biosensors, and Antimicrobial Films.

Degree: PhD, Chemistry, 2017, Vanderbilt University

Recent progress in nanotechnology has enabled rapid expansion at the interface of polymeric systems and biomedicine such that synthetic nanocarriers can be capable of entrapment and tunable releases of chemotherapeutics, improved potential bioavailability and tumor targeting, as well as anti-cancer effects. It has also been shown that chemotherapy by itself is not sufficient to effectively eradicate cancer cells because they can mutate rapidly. Combination therapies which use hydrophobic and hydrophilic protein therapeutics have gained incredible traction in clinical treatments such as combined chemo-immunotherapy, particularly in malignant and drug-resistant cancers. Along with the delivery of biologicals, the need to stabilize biologically active of enzymes in biosensor applications has grown significantly in the last decade. Another pressing biomedical concern is infections that form from biofilm growth on newly implanted hip and knee replacements. A highly advanced and emerging biocompatible polymer called poly(glycidol), also known as poly(glycerol), has a similar polyether backbone to PEG. However, the branching and multiple hydroxyl groups in its chemical structure enable more versatility for bioconjugations, higher hydrophilicity, and outstanding potential in numerous biomedical nanomaterials, biosensing and surface coating applications. Cationic ring-opening polymerizations have been utilized to synthesize poly(glycidols) and poly(esters) as macromolecular building blocks for nano and macro architectures. The poly(ester) polymers were employed for the synthesis of nanosponges and investigated for sustained dual hydrophobic drug delivery and regulated metabolism. Poly(gycidol) architectures were employed for the genesis of a novel nanogel carriers for sustained combination delivery with small hydrophobic and large hydrophilic therapeutics. Through these investigations, poly(glycidol) was employed for a biosensing platform that can immobilize multiple functioning enzymes for improved detection and reusability, and a hydrogel coating was developed to potentially reduce the growth of microbial infections for hip-and knee implants. Advisors/Committee Members: Scott A. Guelcher, Ph.D. (committee member), John A. McLean, Ph.D. (committee member), Steven D. Townsend, Ph.D (committee member), Eva M. Harth, Ph.D. (chair).

Subjects/Keywords: polyglycidol; biosensors; thin film coatings; nanomedicine; nanomaterials

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Lockhart, J. N. (2017). Synthesis of Nanomaterials and Macromolecular Architectures for Dual Drug Delivery Systems, Biosensors, and Antimicrobial Films. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://etd.library.vanderbilt.edu/available/etd-12072017-164241/ ;

Chicago Manual of Style (16th Edition):

Lockhart, Jacob Nathaniel. “Synthesis of Nanomaterials and Macromolecular Architectures for Dual Drug Delivery Systems, Biosensors, and Antimicrobial Films.” 2017. Doctoral Dissertation, Vanderbilt University. Accessed August 14, 2020. http://etd.library.vanderbilt.edu/available/etd-12072017-164241/ ;.

MLA Handbook (7th Edition):

Lockhart, Jacob Nathaniel. “Synthesis of Nanomaterials and Macromolecular Architectures for Dual Drug Delivery Systems, Biosensors, and Antimicrobial Films.” 2017. Web. 14 Aug 2020.

Vancouver:

Lockhart JN. Synthesis of Nanomaterials and Macromolecular Architectures for Dual Drug Delivery Systems, Biosensors, and Antimicrobial Films. [Internet] [Doctoral dissertation]. Vanderbilt University; 2017. [cited 2020 Aug 14]. Available from: http://etd.library.vanderbilt.edu/available/etd-12072017-164241/ ;.

Council of Science Editors:

Lockhart JN. Synthesis of Nanomaterials and Macromolecular Architectures for Dual Drug Delivery Systems, Biosensors, and Antimicrobial Films. [Doctoral Dissertation]. Vanderbilt University; 2017. Available from: http://etd.library.vanderbilt.edu/available/etd-12072017-164241/ ;


Vanderbilt University

2. Keithly, Mary Elizabeth. Structure, substrate selectivity, and catalytic mechanism of the fosfomycin resistance enzyme, FosB, from Gram-positive pathogens.

Degree: PhD, Chemistry, 2016, Vanderbilt University

Structure, substrate selectivity, and catalytic mechanism of the fosfomycin resistance enzyme, FosB, from Gram-positive pathogens By: Mary E. Keithly Fosfomycin, a broad spectrum antibiotic, is used clinically to treat lower urinary tract infections and gastrointestinal infections and has been suggested as part of a regimen for treatment of multi-drug resistant bacterial infections. However, bacterial fosfomycin resistance enzymes limit the efficacy of the antibiotic. A better understanding of the enzymatic mechanism of fosfomycin resistance can contribute to increasing the efficacy and use of fosfomycin. One resistance enzyme, FosB, is a Mn2+-dependent thiol-transferase found in Gram-positive bacteria. FosB modifies fosfomycin by catalyzing nucleophilic addition of a thiol, resulting in an inactive compound. In vitro time course kinetic analyses for FosB from four different bacterial strains using L-cysteine and bacillithiol (BSH) reveal a preference for BSH over L-cysteine. Probing metal dependent activation of FosB by Ni2+, Mg2+, Zn2+, and Mn2+ revealed the highest activation of FosB with Mn2+ as the metal cofactor, whereas Zn2+ inhibits FosB enzymes. I concluded that FosB is a Mn2+-dependent BSH-transferase. Fourteen high-resolution crystal structures of FosB from both Bacillus cereus and Staphylococcus aureus have been determined in complex with various substrates, divalent metals, and products. These structures confirm that FosB is a member of the Vicinal Oxygen Chelate (VOC) superfamily of enzymes. Additionally, a cage of conserved residues orients fosfomycin in the active site such that it is poised for nucleophilic attack by the thiol. The structures also reveal a BSH binding pocket and suggest a highly conserved loop region must change conformation for fosfomycin to enter the active site. Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS) experiments were utilized to investigate the structural dynamics of FosB. HDX-MS data analysis for this enzyme incubated with various substrates and cofactors indicates that FosB is a highly stable globular protein. Moreover, low signal-to-noise for the conserved loop region made analysis of the dynamics of this area difficult to assess with HDX-MS. These observations suggest nuclear magnetic resonance (NMR) should be applied to investigate the critical loop movement of FosB. Advisors/Committee Members: Walter J. Chazin, Ph.D. (chair), Richard N. Armstrong, Ph.D. (Deceased June 2015) (chair), Gary A. Sulikowski, Ph.D. (committee member), Brian O. Bachmann, Ph.D. (committee member), Charles R. Sanders, Ph.D. (committee member), John A. McLean, Ph.D. (committee member).

Subjects/Keywords: Microbial antibiotic resistance; fosfomycin; FosB; Gram-positive

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Keithly, M. E. (2016). Structure, substrate selectivity, and catalytic mechanism of the fosfomycin resistance enzyme, FosB, from Gram-positive pathogens. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://etd.library.vanderbilt.edu/available/etd-07072016-115310/ ;

Chicago Manual of Style (16th Edition):

Keithly, Mary Elizabeth. “Structure, substrate selectivity, and catalytic mechanism of the fosfomycin resistance enzyme, FosB, from Gram-positive pathogens.” 2016. Doctoral Dissertation, Vanderbilt University. Accessed August 14, 2020. http://etd.library.vanderbilt.edu/available/etd-07072016-115310/ ;.

MLA Handbook (7th Edition):

Keithly, Mary Elizabeth. “Structure, substrate selectivity, and catalytic mechanism of the fosfomycin resistance enzyme, FosB, from Gram-positive pathogens.” 2016. Web. 14 Aug 2020.

Vancouver:

Keithly ME. Structure, substrate selectivity, and catalytic mechanism of the fosfomycin resistance enzyme, FosB, from Gram-positive pathogens. [Internet] [Doctoral dissertation]. Vanderbilt University; 2016. [cited 2020 Aug 14]. Available from: http://etd.library.vanderbilt.edu/available/etd-07072016-115310/ ;.

Council of Science Editors:

Keithly ME. Structure, substrate selectivity, and catalytic mechanism of the fosfomycin resistance enzyme, FosB, from Gram-positive pathogens. [Doctoral Dissertation]. Vanderbilt University; 2016. Available from: http://etd.library.vanderbilt.edu/available/etd-07072016-115310/ ;

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