Bi-functional alginate oligosaccharide–polymyxin conjugates for improved treatment of multidrug-resistant gram-negative bacterial infections

Stokniene, Joana, Powell, Lydia C. ORCID: https://orcid.org/0000-0002-8641-0160, Aarstad, Olav A., Aachmann, Finn L., Rye, Philip D., Hill, Katja E. ORCID: https://orcid.org/0000-0002-8590-0117, Thomas, David W. ORCID: https://orcid.org/0000-0001-7319-5820 and Ferguson, Elaine L. ORCID: https://orcid.org/0000-0002-0125-0234 2020. Bi-functional alginate oligosaccharide–polymyxin conjugates for improved treatment of multidrug-resistant gram-negative bacterial infections. Pharmaceutics 12 (11) , 1080. 10.3390/pharmaceutics12111080

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry
Additional Information:	This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Publisher:	MDPI
ISSN:	1999-4923
Funders:	MRC
Date of First Compliant Deposit:	17 November 2020
Date of Acceptance:	9 November 2020
Last Modified:	11 Oct 2023 20:03
URI:	https://orca.cardiff.ac.uk/id/eprint/136425

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