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Development of New Novel Bacterial Topoisomerase Inhibitors as Promising Antibiotics with a 5-Amino-1,3-dioxane Linker Moiety

Li, Linsen
http://rave.ohiolink.edu/etdc/view?acc_num=osu156336340053257

Abstract Details

2019, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
Multidrug-resistant bacteria (MDR) have become one of the greatest threats to human beings. Regardless of the mechanism of action involved, resistance has eventually developed after the clinical use of each class of antibiotics. Thus, new antibiotic classes with unprecedented mechanisms of action are in urgent demand. With a distinct mechanism of action, Novel Bacterial Topoisomerase Inhibitors (NBTIs) represent a promising new class of antibiotics. The recent development of NBTIs has been encouraging. Several NBTIs have processed to clinical trials, and one NBTI (Gepotidacin) has successfully completed Phase 2 clinical trials. However, the cardiac toxicity from the inhibition of hERG K+ channels is one of the major challenges in the discovery of NBTIs. In this work, a 5-amino-1,3-dioxane linker moiety was incorporated in new NBTIs to decrease hERG inhibition, which was demonstrated by comparison with several structure-matched pairs with other linker moieties. A variety of NBTIs with a 5-amino-1,3-dioxane linker have been synthesized and evaluated. Many of these newly synthesized NBTIs showed potent antibacterial activity, covering methicillin-resistant Staphylococcus aureus (MRSA) and fluoroquinolone-resistant strains. Some of these new NBTIs displayed dual inhibition against both DNA gyrase and topoisomerase IV of S. aureus, but they targeted DNA gyrase more potently than topoisomerase IV. These new NBTIs presented low toxicity to human cells and minimal inhibition of human topoisomerase IIα. Additionally, several new NBTIs revealed favorable hERG profiles. With promising preclinical attributes, some of these NBTIs have the potential to be evaluated in in vivo experiments and can serve as the starting point for further development of new NBTIs.
Mark Mitton-Fry (Advisor)
Karl Werbovetz (Committee Member)
Mireia Guerau-de-Arellano (Committee Member)
James Fuchs (Committee Member)
202 p.
Pharmacy Sciences

Recommended Citations

Citations

  • Li, L. (2019). Development of New Novel Bacterial Topoisomerase Inhibitors as Promising Antibiotics with a 5-Amino-1,3-dioxane Linker Moiety [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu156336340053257

    APA Style (7th edition)

  • Li, Linsen. Development of New Novel Bacterial Topoisomerase Inhibitors as Promising Antibiotics with a 5-Amino-1,3-dioxane Linker Moiety. 2019. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu156336340053257.

    MLA Style (8th edition)

  • Li, Linsen. "Development of New Novel Bacterial Topoisomerase Inhibitors as Promising Antibiotics with a 5-Amino-1,3-dioxane Linker Moiety." Doctoral dissertation, Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu156336340053257

    Chicago Manual of Style (17th edition)

osu156336340053257
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© 2019, some rights reserved.Creative Commons License Development of New Novel Bacterial Topoisomerase Inhibitors as Promising Antibiotics with a 5-Amino-1,3-dioxane Linker Moiety by Linsen Li is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.