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Cationic Polysaccharide Conjugates as Antibiotic Adjuvants Resensitize Multidrug-Resistant Bacteria and Prevent
Shaowei Mu1, Yiwen Zhu1, Yu Wang1
1State Key Laboratory of Chemical Resource Engineering Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology, Ministry of Education) and Laboratory of Biomedical Materials, Beijing Advanced Innovation Centre for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, P. R. China.
Abstract:
In recent years, traditional antibiotic efficacy has rapidly diminished due to the advent of multidrug-resistant (MDR) bacteria, which poses severe threat to human life and globalized healthcare. Currently, the development cycle of new antibiotics cannot match the ongoing MDR infection crisis. Therefore, novel strategies are required to resensitize MDR bacteria to existing antibiotics. In this study, novel cationic polysaccharide conjugates Dextran-graft-poly(5-(1,2-dithiolan-3-yl)-N-(2-guanidinoethyl)pentanamide) (Dex-g-PSSn ) is synthesized using disulfide exchange polymerization. Critically, bacterial membranes and efflux pumps are disrupted by a sub-inhibitory concentration of Dex-g-PSS30 , which enhances rifampicin (RIF) accumulation inside bacteria and restores its efficacy. Combined Dex-g-PSS30 and RIF prevents bacterial resistance in bacteria cultured over 30 generations. Furthermore, Dex-g-PSS30 restores RIF effectiveness, reduces inflammatory reactions in a pneumonia-induced mouse model, and exhibits excellent in vivo biological absorption and degradation capabilities. As an antibiotic adjuvant, Dex-g-PSS30 provides a novel resensitizing strategy for RIF against MDR bacteria and bacterial resistance. This Dex-g-PSS30 research provides a solid platform for future MDR applications.
Insights
A novel cationic polysaccharide conjugate, Dex-g-PSS30, resensitizes multidrug-resistant (MDR) bacteria to rifampicin (RIF). This adjuvant therapy restores RIF efficacy, prevents resistance, and shows promise for treating MDR infections.
Area of Science:
- Biochemistry
- Materials Science
- Microbiology
Background:
- Multidrug-resistant (MDR) bacteria pose a significant global health threat due to diminishing antibiotic efficacy.
- The development of new antibiotics lags behind the rapid emergence of MDR infections.
- Novel strategies are urgently needed to resensitize MDR bacteria to existing antibiotics.
Purpose of the Study:
- To synthesize and evaluate a novel cationic polysaccharide conjugate, Dextran-graft-poly(5-(1,2-dithiolan-3-yl)-N-(2-guanidinoethyl)pentanamide) (Dex-g-PSSn), as an antibiotic adjuvant.
- To investigate the potential of Dex-g-PSS30 to restore the efficacy of rifampicin (RIF) against MDR bacteria.
- To assess the in vivo efficacy and safety of Dex-g-PSS30 in a pneumonia mouse model.
Main Methods:
- Synthesis of Dex-g-PSSn via disulfide exchange polymerization.
- Assessment of Dex-g-PSS30's effect on bacterial membrane integrity and efflux pump activity.
- Evaluation of RIF accumulation in bacteria treated with Dex-g-PSS30.
- Testing of combined Dex-g-PSS30 and RIF efficacy in vitro over 30 generations.
- In vivo studies using a pneumonia-induced mouse model to assess therapeutic effects and biodegradation.
Main Results:
- Dex-g-PSS30, at sub-inhibitory concentrations, disrupts bacterial membranes and efflux pumps.
- This disruption enhances intracellular RIF accumulation and restores RIF efficacy against MDR bacteria.
- Combined therapy with Dex-g-PSS30 and RIF prevented the development of bacterial resistance over extended culture periods.
- Dex-g-PSS30 demonstrated in vivo efficacy in reducing inflammation in a pneumonia model and exhibited favorable absorption and degradation profiles.
Conclusions:
- Dex-g-PSS30 acts as an effective antibiotic adjuvant, resensitizing MDR bacteria to RIF.
- This novel strategy offers a promising approach to combatting MDR infections and overcoming antibiotic resistance.
- The study provides a strong foundation for the future development of Dex-g-PSS30 in clinical MDR applications.
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