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Carbohydrates in the Design and Delivery of Antimicrobials.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Carbohydrates in the Design and Delivery of Antimicrobials./
Author:	Wu, Bin .
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
Description:	273 p.
Notes:	Source: Dissertations Abstracts International, Volume: 81-12, Section: B.
Contained By:	Dissertations Abstracts International81-12B.
Subject:	Pharmaceutical sciences. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27736305
ISBN:	9798645465155

Carbohydrates in the Design and Delivery of Antimicrobials.
Wu, Bin .

Carbohydrates in the Design and Delivery of Antimicrobials. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 273 p.

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

Thesis (Ph.D.)--University of Massachusetts Lowell, 2020.

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

This thesis focuses on developing carbohydrate-based targeted antibiotic delivery systems and modification of known antibiotics to enhance their antibacterial activity. This work is divided into four parts and is summarized below. In Chapter 2, maltoheptaose (G7) was applied as the targeting ligands on liposomes to enhnace the delivery of antibiotics to E. coli. A G7-lipid as well as Man (mannose)-lipid were synthesized by coupling G7 or Man to the lipid DPPE, and subsequently used to formulate carbohydrate-presenting liposomes. A lectin (Concanavalin A) binding assay was carried out to confirm the presence of carbohydrates on the liposomes. After loading with antibiotic, their antimicrobial activities and time-kill studies were carried out on E. coli. The rifampin-loaded G7-presenting fluidic liposomes showed 3 times lower MIC compared to rifampin against E. coli. Most importantly, it reduced bacteria colonies by 2 logs over 24 h at 4xMIC compared to no changes for rifampin or the non-fluidic liposome formulation. Fluorescence resonance energy transfer (FRET) experiments suggested stronger binding of G7-liposomes to the bacteria, which may contribute to the enhanced bacteria killing. Chapter 3 focuses on the synthesis of carbohydrate-grafted cyclodextrin (CD) as the drug delivery system. The bacteria targeting carbohydrates, maltose to E. coli and trehlaose to M. smegmatis, were conjugated to β-CD to give corresponding Mal-CD and Tre-CD. Antibiotics were subsequently incoporated in the β-CD, Mal-CD and Tre-CD, and the resulting cyclodextrin-antibiotic complexes were studied by 1H NMR. Our data suggest that both β-CD and Mal-CD encapsulated doxycycline from its aromatic side. Rifampin seemed to be encapsulated at the methyl ester side into β-CD and Mal-CD, not at the piperazine ring side like in the case of β-CD. In addition, the β-lactam ring of penicillin G and amipicillin appears to be encapsulated in the cavity of Mal-CD and Tre-CD. Preliminary results showed that these cyclodextrin-antibiotic complexes exhibited the same potent antibacterial activities as the free drug.Chapter 4 focuses on the comprehensive structure-activity relationship (SAR) study of auranofin, an Au(I)-based FDA-approved anti- arthritis drug. Auranofin was recently re-purposed as an antimicrobial but was only effective against Gram-positive bacteria. In this work, a library of auranofin analogues was synthesized by varying the structures of the thiol and phosphine ligands on Au(I). Their antibacterial activities were tested against ESKAPE pathogens and E. coli. The lead compounds exhibited activities up to 65 folds higher than that of auranofin, making them effective against Gram-negative pathogens. Additionally, auranofin analogues with thio GlcNAc ligand were selected to test their activities against H. pylori, a Gram-negative pathogen colonized in the stomach and can cause chronic gastritis. The hope was that these analogues could be robustly uptaken in a similar way as GlcNAc, which was known to be selectively transported by H. pylori. Results showed that all these thio GlcNAc-modified auranofin analogues displayed potent activities against H. pylori with an MIC in the micromolar range.Chapter 5 is to explore the feasibility of utilizing carbohydrate transport pathways to deliver ciprofloxacin. Maltose and trehalose, having well-studied transport pathways, were conjugated to ciprofloxacin via the click reaction. Their antibacterial activities were then tested against E. coli, S.epidermidis and M. smegmatis. The maltose C-1 conjugate and trehalose conjugates exhibited slightly higher activities than the control which is the ethyl alcohol conjugate. The maltose C-3 conjugate showed 5-25 times higher bacteria growth inhibition compared to the maltose C-1 conjugate, indicating the glycosylated ciprofloxacin might be actively transported by the bacteria.

ISBN: 9798645465155Subjects--Topical Terms:

1180569
Pharmaceutical sciences.
Subjects--Index Terms:

Antibacterial activity

Carbohydrates in the Design and Delivery of Antimicrobials.
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245 1 0 $a Carbohydrates in the Design and Delivery of Antimicrobials.
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300 $a 273 p.
500 $a Source: Dissertations Abstracts International, Volume: 81-12, Section: B.
500 $a Advisor: Yan, Mingdi.
502 $a Thesis (Ph.D.)--University of Massachusetts Lowell, 2020.
506 $a This item must not be sold to any third party vendors.
520 $a This thesis focuses on developing carbohydrate-based targeted antibiotic delivery systems and modification of known antibiotics to enhance their antibacterial activity. This work is divided into four parts and is summarized below. In Chapter 2, maltoheptaose (G7) was applied as the targeting ligands on liposomes to enhnace the delivery of antibiotics to E. coli. A G7-lipid as well as Man (mannose)-lipid were synthesized by coupling G7 or Man to the lipid DPPE, and subsequently used to formulate carbohydrate-presenting liposomes. A lectin (Concanavalin A) binding assay was carried out to confirm the presence of carbohydrates on the liposomes. After loading with antibiotic, their antimicrobial activities and time-kill studies were carried out on E. coli. The rifampin-loaded G7-presenting fluidic liposomes showed 3 times lower MIC compared to rifampin against E. coli. Most importantly, it reduced bacteria colonies by 2 logs over 24 h at 4xMIC compared to no changes for rifampin or the non-fluidic liposome formulation. Fluorescence resonance energy transfer (FRET) experiments suggested stronger binding of G7-liposomes to the bacteria, which may contribute to the enhanced bacteria killing. Chapter 3 focuses on the synthesis of carbohydrate-grafted cyclodextrin (CD) as the drug delivery system. The bacteria targeting carbohydrates, maltose to E. coli and trehlaose to M. smegmatis, were conjugated to β-CD to give corresponding Mal-CD and Tre-CD. Antibiotics were subsequently incoporated in the β-CD, Mal-CD and Tre-CD, and the resulting cyclodextrin-antibiotic complexes were studied by 1H NMR. Our data suggest that both β-CD and Mal-CD encapsulated doxycycline from its aromatic side. Rifampin seemed to be encapsulated at the methyl ester side into β-CD and Mal-CD, not at the piperazine ring side like in the case of β-CD. In addition, the β-lactam ring of penicillin G and amipicillin appears to be encapsulated in the cavity of Mal-CD and Tre-CD. Preliminary results showed that these cyclodextrin-antibiotic complexes exhibited the same potent antibacterial activities as the free drug.Chapter 4 focuses on the comprehensive structure-activity relationship (SAR) study of auranofin, an Au(I)-based FDA-approved anti- arthritis drug. Auranofin was recently re-purposed as an antimicrobial but was only effective against Gram-positive bacteria. In this work, a library of auranofin analogues was synthesized by varying the structures of the thiol and phosphine ligands on Au(I). Their antibacterial activities were tested against ESKAPE pathogens and E. coli. The lead compounds exhibited activities up to 65 folds higher than that of auranofin, making them effective against Gram-negative pathogens. Additionally, auranofin analogues with thio GlcNAc ligand were selected to test their activities against H. pylori, a Gram-negative pathogen colonized in the stomach and can cause chronic gastritis. The hope was that these analogues could be robustly uptaken in a similar way as GlcNAc, which was known to be selectively transported by H. pylori. Results showed that all these thio GlcNAc-modified auranofin analogues displayed potent activities against H. pylori with an MIC in the micromolar range.Chapter 5 is to explore the feasibility of utilizing carbohydrate transport pathways to deliver ciprofloxacin. Maltose and trehalose, having well-studied transport pathways, were conjugated to ciprofloxacin via the click reaction. Their antibacterial activities were then tested against E. coli, S.epidermidis and M. smegmatis. The maltose C-1 conjugate and trehalose conjugates exhibited slightly higher activities than the control which is the ethyl alcohol conjugate. The maltose C-3 conjugate showed 5-25 times higher bacteria growth inhibition compared to the maltose C-1 conjugate, indicating the glycosylated ciprofloxacin might be actively transported by the bacteria.
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