التفاصيل البيبلوغرافية
| العنوان: |
Bi-Functional Alginate Oligosaccharide–Polymyxin Conjugates for Improved Treatment of Multidrug-Resistant Gram-Negative Bacterial Infections |
| المؤلفون: |
Joana Stokniene, Lydia C. Powell, Olav A. Aarstad, Finn L. Aachmann, Philip D. Rye, Katja E. Hill, David W. Thomas, Elaine L. Ferguson |
| المصدر: |
Pharmaceutics; Volume 12; Issue 11; Pages: 1080 |
| بيانات النشر: |
Multidisciplinary Digital Publishing Institute |
| سنة النشر: |
2020 |
| المجموعة: |
MDPI Open Access Publishing |
| مصطلحات موضوعية: |
gram-negative bacteria, multidrug resistance, polymer therapeutics, colistin, polymyxin B |
| الوصف: |
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. |
| نوع الوثيقة: |
text |
| وصف الملف: |
application/pdf |
| اللغة: |
English |
| Relation: |
Drug Delivery and Controlled Release; https://dx.doi.org/10.3390/pharmaceutics12111080 |
| DOI: |
10.3390/pharmaceutics12111080 |
| الاتاحة: |
https://doi.org/10.3390/pharmaceutics12111080 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: |
edsbas.4FF96A1A |
| قاعدة البيانات: |
BASE |