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

Bibliographic Details
Main Author:	Li, Linsen
Language:	English
Published:	The Ohio State University / OhioLINK 2019
Subjects:	Pharmacy Sciences
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=osu156336340053257

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-osu1563363400532572021-08-03T07:11:54Z Development of New Novel Bacterial Topoisomerase Inhibitors as Promising Antibiotics with a 5-Amino-1,3-dioxane Linker Moiety Li, Linsen Pharmacy 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. 2019-11-15 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu156336340053257 http://rave.ohiolink.edu/etdc/view?acc_num=osu156336340053257 unrestricted This thesis or dissertation is protected by copyright: some rights reserved. It is licensed for use under a Creative Commons license. Specific terms and permissions are available from this document's record in the OhioLINK ETD Center.
collection	NDLTD
language	English
sources	NDLTD
topic	Pharmacy Sciences
spellingShingle	Pharmacy Sciences Li, Linsen Development of New Novel Bacterial Topoisomerase Inhibitors as Promising Antibiotics with a 5-Amino-1,3-dioxane Linker Moiety
author	Li, Linsen
author_facet	Li, Linsen
author_sort	Li, Linsen
title	Development of New Novel Bacterial Topoisomerase Inhibitors as Promising Antibiotics with a 5-Amino-1,3-dioxane Linker Moiety
title_short	Development of New Novel Bacterial Topoisomerase Inhibitors as Promising Antibiotics with a 5-Amino-1,3-dioxane Linker Moiety
title_full	Development of New Novel Bacterial Topoisomerase Inhibitors as Promising Antibiotics with a 5-Amino-1,3-dioxane Linker Moiety
title_fullStr	Development of New Novel Bacterial Topoisomerase Inhibitors as Promising Antibiotics with a 5-Amino-1,3-dioxane Linker Moiety
title_full_unstemmed	Development of New Novel Bacterial Topoisomerase Inhibitors as Promising Antibiotics with a 5-Amino-1,3-dioxane Linker Moiety
title_sort	development of new novel bacterial topoisomerase inhibitors as promising antibiotics with a 5-amino-1,3-dioxane linker moiety
publisher	The Ohio State University / OhioLINK
publishDate	2019
url	http://rave.ohiolink.edu/etdc/view?acc_num=osu156336340053257
work_keys_str_mv	AT lilinsen developmentofnewnovelbacterialtopoisomeraseinhibitorsaspromisingantibioticswitha5amino13dioxanelinkermoiety
_version_	1719455861812756480

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

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