자료유형  

 학위논문

Control Number  

0017162303

International Standard Book Number  

9798383595411

Dewey Decimal Classification Number  

540

Main Entry-Personal Name  

Jones, Chelsea Rae.

Publication, Distribution, etc. (Imprint  

[S.l.] : University of California, Irvine., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

207 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-02, Section: B.

General Note  

Advisor: Nowick, James S.

Dissertation Note  

Thesis (Ph.D.)--University of California, Irvine, 2024.

Summary, Etc.  

요약In my thesis I aim to develop novel antibiotics in the fight against Gram-positive bacteria. In Chapter 1, I summarize the outlook of antibiotic resistance and how a new antibiotic, teixobactin, serves as a promising antibiotic candidate for drug development. I provide a summary on the mechanism of action of teixobactin, structure-activity relationship studies of teixobactin, and the limitations of teixobactin as an antibiotic drug candidate. In the last section of Chapter 1, I review isoacyl motifs and their use in the development of prodrugs and in the synthesis of aggregation-prone peptide sequences.In Chapter 2, I introduce my work in the design and development of O-acyl isopeptide prodrugs of teixobactin analogues, which we have termed isobactins, to overcome the limitations of teixobactin. The antibiotic teixobactin is a promising drug candidate against drug-resistance pathogens, such as MRSA and VRE, but forms insoluble gels that may limit intravenous administration. O-Acyl isopeptide prodrug analogues of teixobactin circumvent the problem of gel formation while retaining antibiotic activity. The teixobactin prodrug analogues contain ester linkages between Ile6 and Ser7, Ile2 and Ser3, or between both Ile6 and Ser7 and Ile2 and Ser3. Upon exposure to physiological pH, the prodrug analogues undergo clean conversion to the corresponding amides, with half-lives between 13 and 115 min. Prodrug analogues containing lysine, arginine, or leucine at position 10 exhibit good antibiotic activity against a variety of Gram-positive bacteria while exhibiting little or no cytotoxicity or hemolytic activity. Because O-acyl isopeptide prodrug analogues of teixobactin exhibit clean conversion to the corresponding teixobactin analogues with a reduced propensity to form gels, it is anticipated that teixobactin prodrugs will be superior to teixobactin as drug candidates. In Chapter 3, I present my work in the investigation of additional isobactin analogues of teixobactin. I present nine new isobactin analogues that exhibit a reduced propensity to form gels in aqueous conditions while maintaining potent antibiotic activity against MRSA, VRE, and other Gram-positive bacteria. These isobactin analogues contain commercially available amino acid residues at position 10, replacing the synthetically challenging L-allo-enduracididine residue that is present in teixobactin. The isobactins undergo clean conversion to their corresponding teixobactin analogues at physiological pH and exhibit little to no hemolytic activity or cytotoxicity. Because isobactin analogues exhibit enhanced solubility, delayed gel formation, and are more synthetically accessible, it is anticipated that isobactin prodrug analogues may be superior drug candidates to teixobactin.In Chapter 4, I describe my efforts towards the synthesis of natural teixobactin and isobactins A, B, and C. The previous two chapters highlight the design of prodrugs of teixobactin analogues, which replace the synthetically challenging L-allo-enduracididine residue at position 10 with commercially available amino acids. Therefore, to obtain natural teixobactin and the prodrugs of teixobactin, isobactins A, B, and C, the native L-allo-enduracididine residue must be introduced. Chapter 4 describes the efforts in the synthesis of L-allo-enduracididine and the synthesis of natural teixobactin and isobactins A, B, and C. This chapter serves as the groundwork for future graduate students that may work on the synthesis of these isobactins.

Subject Added Entry-Topical Term  

Chemistry.

Subject Added Entry-Topical Term  

Biochemistry.

Subject Added Entry-Topical Term  

Organic chemistry.

Index Term-Uncontrolled  

Peptide

Index Term-Uncontrolled  

Prodrug

Index Term-Uncontrolled  

Teixobactin

Index Term-Uncontrolled  

Isobactins

Added Entry-Corporate Name  

University of California, Irvine Chemistry

Host Item Entry  

Dissertations Abstracts International. 86-02B.

Electronic Location and Access  

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Control Number  

joongbu:655831