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Metallophores as Tools for Antibioti...

Cao, Minhua,

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Metallophores as Tools for Antibiotic Drug Development and the Study of Bacterial Metal Homeostasis /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Metallophores as Tools for Antibiotic Drug Development and the Study of Bacterial Metal Homeostasis // Minhua Cao.
Author:	Cao, Minhua,
Description:	1 electronic resource (243 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-11, Section: B.
Contained By:	Dissertations Abstracts International86-11B.
Subject:	Chemistry. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=32042172
ISBN:	9798314895610

Metallophores as Tools for Antibiotic Drug Development and the Study of Bacterial Metal Homeostasis /
Cao, Minhua,

Metallophores as Tools for Antibiotic Drug Development and the Study of Bacterial Metal Homeostasis /Minhua Cao. - 1 electronic resource (243 pages)

Source: Dissertations Abstracts International, Volume: 86-11, Section: B.

Antibiotic resistance poses a critical global health threat, contributing to an estimated 4.95 million deaths in 2019 alone. The efficacy of conventional antibiotics is increasingly compromised by the emergence of resistant strains, limiting treatment options. To circumvent these resistance mechanisms, alternative strategies are being explored, including the use of siderophores, microbe secondary metabolite, to hijack bacterial iron import pathways for cytotoxic payload delivery inspired by natural antibiotics. This approach has gained significant traction, exemplified by the FDA approval of Cefiderocol, a siderophore antibiotic, and extensive efforts to develop other siderophore-based antibiotics. However, our knowledge of the uptake and stability of these compounds remains incomplete.To advance our understanding of siderophore uptake and stability, we developed and applied radiolabeled and photoaffinity-labeled small molecule tools. First, we developed a dual radiolabeling strategy using 67Ga and 124I to track both in vitro and in vivo behavior. This revealed that Ga siderophore conjugates are internalized as metal complexes via siderophore-mediated uptake. In vivo studies, utilizing a murine infection model, demonstrated probe degradation primarily through metal cargo decomplexation, though Ga-D6-I exhibited significant uptake in infected tissue (Chapter 2). Second, based on the Fe-D1/FoxA co-crystal structure, we designed and optimized photoaffinity probes to understand their reactivity and validate their ability to target siderophore transmembrane transporters. These probes successfully labeled isolated FoxA protein (Chapter 3). Third, when applied to live bacterial cells, these probes facilitated the visualization and identification of siderophore-binding proteins, suggesting a potential role for OmpF in the uptake of these compounds (Chapter 4). Overall, this research provides valuable insights into the stability and uptake mechanisms of Ga-siderophore conjugates, offering new tools and strategies for future studies on siderophore-antibiotic acquisition and pharmacokinetics.

English

ISBN: 9798314895610Subjects--Topical Terms:

516420
Chemistry.
Subjects--Index Terms:

Iron uptake

Metallophores as Tools for Antibiotic Drug Development and the Study of Bacterial Metal Homeostasis /
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520 $a Antibiotic resistance poses a critical global health threat, contributing to an estimated 4.95 million deaths in 2019 alone. The efficacy of conventional antibiotics is increasingly compromised by the emergence of resistant strains, limiting treatment options. To circumvent these resistance mechanisms, alternative strategies are being explored, including the use of siderophores, microbe secondary metabolite, to hijack bacterial iron import pathways for cytotoxic payload delivery inspired by natural antibiotics. This approach has gained significant traction, exemplified by the FDA approval of Cefiderocol, a siderophore antibiotic, and extensive efforts to develop other siderophore-based antibiotics. However, our knowledge of the uptake and stability of these compounds remains incomplete.To advance our understanding of siderophore uptake and stability, we developed and applied radiolabeled and photoaffinity-labeled small molecule tools. First, we developed a dual radiolabeling strategy using 67Ga and 124I to track both in vitro and in vivo behavior. This revealed that Ga siderophore conjugates are internalized as metal complexes via siderophore-mediated uptake. In vivo studies, utilizing a murine infection model, demonstrated probe degradation primarily through metal cargo decomplexation, though Ga-D6-I exhibited significant uptake in infected tissue (Chapter 2). Second, based on the Fe-D1/FoxA co-crystal structure, we designed and optimized photoaffinity probes to understand their reactivity and validate their ability to target siderophore transmembrane transporters. These probes successfully labeled isolated FoxA protein (Chapter 3). Third, when applied to live bacterial cells, these probes facilitated the visualization and identification of siderophore-binding proteins, suggesting a potential role for OmpF in the uptake of these compounds (Chapter 4). Overall, this research provides valuable insights into the stability and uptake mechanisms of Ga-siderophore conjugates, offering new tools and strategies for future studies on siderophore-antibiotic acquisition and pharmacokinetics.
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650 4 $a Pharmacology. $3 634543
650 4 $a Biomedical engineering. $3 535387
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653 $a Iron uptake
653 $a Siderophores
653 $a Siderophore antibiotic
653 $a Antibiotic resistance
653 $a Pharmacokinetics
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