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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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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)) 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.
Keywords: gram-negative bacteria; multidrug resistance; polymer therapeutics; colistin; polymyxin B
College: Faculty of Medicine, Health and Life Sciences
Funders: 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).
Issue: 11
Start Page: 1080

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