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Structure, Function, and Inhibition of Aerobactin Biosynthesis from Hypervirulent Klebsiella pneumoniae.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Structure, Function, and Inhibition of Aerobactin Biosynthesis from Hypervirulent Klebsiella pneumoniae./
Author:	Bailey, Daniel Curtis.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
Description:	185 p.
Notes:	Source: Dissertations Abstracts International, Volume: 81-12, Section: B.
Contained By:	Dissertations Abstracts International81-12B.
Subject:	Biochemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10830925
ISBN:	9798617024304

Structure, Function, and Inhibition of Aerobactin Biosynthesis from Hypervirulent Klebsiella pneumoniae.
Bailey, Daniel Curtis.

Structure, Function, and Inhibition of Aerobactin Biosynthesis from Hypervirulent Klebsiella pneumoniae. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 185 p.

Source: Dissertations Abstracts International, Volume: 81-12, Section: B.

Thesis (Ph.D.)--State University of New York at Buffalo, 2020.

This item must not be sold to any third party vendors.

Since it was initially described in the mid-1980s in the Asian Pacific Rim, a hypervirulent pathotype of Klebsiella pneumoniae (hvKP) has disseminated throughout the globe. In contrast to classical opportunistic strains of Klebsiella pneumoniae, hvKP is able to cause serious life-threatening infections in previously healthy individuals in the community. Recent reports have confirmed fears within the medical community that the convergence of multi-drug resistant and hypervirulent KP pathotypes has led to the evolution of a highly transmissible, drug resistant, and virulent "super bug". Contemporary investigations toward understanding the enhanced virulence of hvKP strains have highlighted the importance of the biosynthesis of the siderophore aerobactin. Siderophores are small molecule iron-chelators that allow bacteria to assimilate sufficient quantities of this vital nutrient in the often severely iron-limited host environment.With an ever-increasing demand for novel therapeutic approaches for treating Gram-negative infections, we hypothesized aerobactin could be a viable "antivirulence" target for the treatment of infections with hvKP and other pathogens that rely on this siderophore. The research presented herein focused on three general topics: (1) demonstrating the function of the enzymes required to biosynthesize aerobactin, (2) characterizing the structure of the aerobactin synthetase enzymes IucA and IucC, and (3) the developing a high-throughput screening platform for identifying novel small-molecule inhibitors of aerobactin biosynthesis.To lay the foundation, the aerobactin biosynthetic pathway was first functionally demonstrated in vitro using purified enzymes. X-ray crystallography and solution scattering analyses were employed to structurally characterize IucA and IucC, which were combined with a number of biochemical studies to propose a molecular catalytic mechanism for these enzymes. Finally, leveraging our functional and structural knowledge of IucA, a high-throughput biochemical assay was developed and employed to screen over 110,00 compounds for antagonism of IucA catalysis; identifying a number of inhibitors with in vitro activity at low-micromolar concentrations.

ISBN: 9798617024304Subjects--Topical Terms:

518028
Biochemistry.
Subjects--Index Terms:

Aerobactin

Structure, Function, and Inhibition of Aerobactin Biosynthesis from Hypervirulent Klebsiella pneumoniae.
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245 1 0 $a Structure, Function, and Inhibition of Aerobactin Biosynthesis from Hypervirulent Klebsiella pneumoniae.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2020
300 $a 185 p.
500 $a Source: Dissertations Abstracts International, Volume: 81-12, Section: B.
500 $a Advisor: Gulick, Andrew.
502 $a Thesis (Ph.D.)--State University of New York at Buffalo, 2020.
506 $a This item must not be sold to any third party vendors.
506 $a This item must not be added to any third party search indexes.
520 $a Since it was initially described in the mid-1980s in the Asian Pacific Rim, a hypervirulent pathotype of Klebsiella pneumoniae (hvKP) has disseminated throughout the globe. In contrast to classical opportunistic strains of Klebsiella pneumoniae, hvKP is able to cause serious life-threatening infections in previously healthy individuals in the community. Recent reports have confirmed fears within the medical community that the convergence of multi-drug resistant and hypervirulent KP pathotypes has led to the evolution of a highly transmissible, drug resistant, and virulent "super bug". Contemporary investigations toward understanding the enhanced virulence of hvKP strains have highlighted the importance of the biosynthesis of the siderophore aerobactin. Siderophores are small molecule iron-chelators that allow bacteria to assimilate sufficient quantities of this vital nutrient in the often severely iron-limited host environment.With an ever-increasing demand for novel therapeutic approaches for treating Gram-negative infections, we hypothesized aerobactin could be a viable "antivirulence" target for the treatment of infections with hvKP and other pathogens that rely on this siderophore. The research presented herein focused on three general topics: (1) demonstrating the function of the enzymes required to biosynthesize aerobactin, (2) characterizing the structure of the aerobactin synthetase enzymes IucA and IucC, and (3) the developing a high-throughput screening platform for identifying novel small-molecule inhibitors of aerobactin biosynthesis.To lay the foundation, the aerobactin biosynthetic pathway was first functionally demonstrated in vitro using purified enzymes. X-ray crystallography and solution scattering analyses were employed to structurally characterize IucA and IucC, which were combined with a number of biochemical studies to propose a molecular catalytic mechanism for these enzymes. Finally, leveraging our functional and structural knowledge of IucA, a high-throughput biochemical assay was developed and employed to screen over 110,00 compounds for antagonism of IucA catalysis; identifying a number of inhibitors with in vitro activity at low-micromolar concentrations.
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653 $a Enzymology
653 $a Klebsiella pneumoniae
653 $a Siderophore
653 $a Synthetase
653 $a X-ray crystallography
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710 2 $a State University of New York at Buffalo. $b Structural Biology. $3 3685153
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793 $a English
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