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Bi-Functional Alginate Oligosaccharide–Polymyxin Conjugates for Improved Treatment of Multidrug-Resistant Gram-Negative Bacterial Infections

Joana Stokniene, Lydia Powell Orcid Logo, Olav A. Aarstad, Finn L. Aachmann, Philip D. Rye Orcid Logo, Katja E. Hill Orcid Logo, David W. Thomas Orcid Logo, Elaine L. Ferguson

Pharmaceutics, Volume: 12, Issue: 11, Start page: 1080

Swansea University Author: Lydia Powell Orcid Logo

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DOI (Published version): 10.3390/pharmaceutics12111080

Abstract

The recent emergence of resistance to colistin, an antibiotic of last resort with dose-limiting toxicity, has highlighted the need for alternative approaches to combat infection. This study aimed to generate and characterise alginate oligosaccharide (“OligoG”)–polymyxin (polymyxin B and E (colistin)...

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Published in: Pharmaceutics
ISSN: 1999-4923
Published: MDPI AG 2020
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URI: https://cronfa.swan.ac.uk/Record/cronfa61613
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This study aimed to generate and characterise alginate oligosaccharide (&#x201C;OligoG&#x201D;)&#x2013;polymyxin (polymyxin B and E (colistin)) conjugates to improve the effectiveness of these antibiotics. OligoG&#x2013;polymyxin conjugates (amide- or ester-linked), with molecular weights of 5200&#x2013;12,800 g/mol and antibiotic loading of 6.1&#x2013;12.9% w/w, were reproducibly synthesised. In vitro inflammatory cytokine production (tumour necrosis factor alpha (TNF&#x3B1;) ELISA) and cytotoxicity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) of colistin (2.2&#x2013;9.3-fold) and polymyxin B (2.9&#x2013;27.2-fold) were significantly decreased by OligoG conjugation. Antimicrobial susceptibility tests (minimum inhibitory concentration (MIC), growth curves) demonstrated similar antimicrobial efficacy of ester- and amide-linked conjugates to that of the parent antibiotic but with more sustained inhibition of bacterial growth. OligoG&#x2013;polymyxin conjugates exhibited improved selectivity for Gram-negative bacteria in comparison to mammalian cells (approximately 2&#x2013;4-fold). Both OligoG&#x2013;colistin conjugates caused significant disruption of Pseudomonas aeruginosa biofilm formation and induced bacterial death (confocal laser scanning microscopy). When conjugates were tested in an in vitro &#x201C;time-to-kill&#x201D; (TTK) model using Acinetobacter baumannii, only ester-linked conjugates reduced viable bacterial counts (~2-fold) after 4 h. 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spelling 2022-11-09T12:55:27.0611619 v2 61613 2022-10-20 Bi-Functional Alginate Oligosaccharide–Polymyxin Conjugates for Improved Treatment of Multidrug-Resistant Gram-Negative Bacterial Infections 0e7e702952672bcbfdfd4974199202fb 0000-0002-8641-0160 Lydia Powell Lydia Powell true false 2022-10-20 BMS The recent emergence of resistance to colistin, an antibiotic of last resort with dose-limiting toxicity, has highlighted the need for alternative approaches to combat infection. This study aimed to generate and characterise alginate oligosaccharide (“OligoG”)–polymyxin (polymyxin B and E (colistin)) conjugates to improve the effectiveness of these antibiotics. OligoG–polymyxin conjugates (amide- or ester-linked), with molecular weights of 5200–12,800 g/mol and antibiotic loading of 6.1–12.9% w/w, were reproducibly synthesised. In vitro inflammatory cytokine production (tumour necrosis factor alpha (TNFα) ELISA) and cytotoxicity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) of colistin (2.2–9.3-fold) and polymyxin B (2.9–27.2-fold) were significantly decreased by OligoG conjugation. Antimicrobial susceptibility tests (minimum inhibitory concentration (MIC), growth curves) demonstrated similar antimicrobial efficacy of ester- and amide-linked conjugates to that of the parent antibiotic but with more sustained inhibition of bacterial growth. OligoG–polymyxin conjugates exhibited improved selectivity for Gram-negative bacteria in comparison to mammalian cells (approximately 2–4-fold). Both OligoG–colistin conjugates caused significant disruption of Pseudomonas aeruginosa biofilm formation and induced bacterial death (confocal laser scanning microscopy). When conjugates were tested in an in vitro “time-to-kill” (TTK) model using Acinetobacter baumannii, only ester-linked conjugates reduced viable bacterial counts (~2-fold) after 4 h. Bi-functional OligoG–polymyxin conjugates have potential therapeutic benefits in the treatment of multidrug-resistant (MDR) Gram-negative bacterial infections, directly reducing toxicity whilst retaining antimicrobial and antibiofilm activities. Journal Article Pharmaceutics 12 11 1080 MDPI AG 1999-4923 gram-negative bacteria; multidrug resistance; polymer therapeutics; colistin; polymyxin B 11 11 2020 2020-11-11 10.3390/pharmaceutics12111080 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University This work was supported by funding from the Research Council of Norway (228542/O30, 281920 and 226244), AlgiPharma AS, Sandvika, Norway and UK Medical Research Council (MR/N023633/1). 2022-11-09T12:55:27.0611619 2022-10-20T14:21:26.8581828 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Joana Stokniene 1 Lydia Powell 0000-0002-8641-0160 2 Olav A. Aarstad 3 Finn L. Aachmann 4 Philip D. Rye 0000-0001-7762-3300 5 Katja E. Hill 0000-0002-8590-0117 6 David W. Thomas 0000-0001-7319-5820 7 Elaine L. Ferguson 8 61613__25712__14ed3c5ca8114ddaad578499787d3d60.pdf 61613.pdf 2022-11-09T12:53:16.6666383 Output 3720030 application/pdf Version of Record true © 2020 by the authors. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license true eng http://creativecommons.org/licenses/by/4.0/
title Bi-Functional Alginate Oligosaccharide–Polymyxin Conjugates for Improved Treatment of Multidrug-Resistant Gram-Negative Bacterial Infections
spellingShingle Bi-Functional Alginate Oligosaccharide–Polymyxin Conjugates for Improved Treatment of Multidrug-Resistant Gram-Negative Bacterial Infections
Lydia Powell
title_short Bi-Functional Alginate Oligosaccharide–Polymyxin Conjugates for Improved Treatment of Multidrug-Resistant Gram-Negative Bacterial Infections
title_full Bi-Functional Alginate Oligosaccharide–Polymyxin Conjugates for Improved Treatment of Multidrug-Resistant Gram-Negative Bacterial Infections
title_fullStr Bi-Functional Alginate Oligosaccharide–Polymyxin Conjugates for Improved Treatment of Multidrug-Resistant Gram-Negative Bacterial Infections
title_full_unstemmed Bi-Functional Alginate Oligosaccharide–Polymyxin Conjugates for Improved Treatment of Multidrug-Resistant Gram-Negative Bacterial Infections
title_sort Bi-Functional Alginate Oligosaccharide–Polymyxin Conjugates for Improved Treatment of Multidrug-Resistant Gram-Negative Bacterial Infections
author_id_str_mv 0e7e702952672bcbfdfd4974199202fb
author_id_fullname_str_mv 0e7e702952672bcbfdfd4974199202fb_***_Lydia Powell
author Lydia Powell
author2 Joana Stokniene
Lydia Powell
Olav A. Aarstad
Finn L. Aachmann
Philip D. Rye
Katja E. Hill
David W. Thomas
Elaine L. Ferguson
format Journal article
container_title Pharmaceutics
container_volume 12
container_issue 11
container_start_page 1080
publishDate 2020
institution Swansea University
issn 1999-4923
doi_str_mv 10.3390/pharmaceutics12111080
publisher MDPI AG
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description The recent emergence of resistance to colistin, an antibiotic of last resort with dose-limiting toxicity, has highlighted the need for alternative approaches to combat infection. This study aimed to generate and characterise alginate oligosaccharide (“OligoG”)–polymyxin (polymyxin B and E (colistin)) conjugates to improve the effectiveness of these antibiotics. OligoG–polymyxin conjugates (amide- or ester-linked), with molecular weights of 5200–12,800 g/mol and antibiotic loading of 6.1–12.9% w/w, were reproducibly synthesised. In vitro inflammatory cytokine production (tumour necrosis factor alpha (TNFα) ELISA) and cytotoxicity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) of colistin (2.2–9.3-fold) and polymyxin B (2.9–27.2-fold) were significantly decreased by OligoG conjugation. Antimicrobial susceptibility tests (minimum inhibitory concentration (MIC), growth curves) demonstrated similar antimicrobial efficacy of ester- and amide-linked conjugates to that of the parent antibiotic but with more sustained inhibition of bacterial growth. OligoG–polymyxin conjugates exhibited improved selectivity for Gram-negative bacteria in comparison to mammalian cells (approximately 2–4-fold). Both OligoG–colistin conjugates caused significant disruption of Pseudomonas aeruginosa biofilm formation and induced bacterial death (confocal laser scanning microscopy). When conjugates were tested in an in vitro “time-to-kill” (TTK) model using Acinetobacter baumannii, only ester-linked conjugates reduced viable bacterial counts (~2-fold) after 4 h. Bi-functional OligoG–polymyxin conjugates have potential therapeutic benefits in the treatment of multidrug-resistant (MDR) Gram-negative bacterial infections, directly reducing toxicity whilst retaining antimicrobial and antibiofilm activities.
published_date 2020-11-11T04:20:33Z
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