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Peptide-mimicking poly(2-oxazoline)s as adjuvants to enhance activities and antibacterial spectrum of polymyxin B

模拟宿主防御肽的聚(2-噁唑啉)作为佐剂增强多粘菌素B的抗菌活性并拓展抗菌谱

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Abstract

Antibiotic-resistant ESKAPE bacteria have become a significant threat to human health due to the ineffectiveness of clinically used broad-spectrum antibiotics. Combination therapy of antibiotic and adjuvant has emerged as a promising strategy to overcome antibiotic-resistant bacteria. However, the antibiotic-adjuvant combination with potent and broad-spectrum antimicrobial activities against all ESKAPE bacteria remains a huge challenge. Herein, we proposed an effective combination strategy of using polymyxin B (PMB) as the antibiotic, which exhibited potent activity against Gram-negative ESKAPE bacteria, and host defense peptide (HDP)-mimicking cationic antimicrobial poly(2-oxazoline)s that target bacterial membrane as the adjuvant. A series of cationic poly(2-oxazoline)s with varying hydrophobic side chain lengths were synthesized via the controllable 2-oxazoline polymerization. The results indicate that the combination effect of PMB and HDP-mimicking poly(2-oxazoline)s exhibits the gradual change from antagonistic effect to synergistic effect as the hydrophobicity and ability to disrupt bacterial membrane of poly(2-oxazoline)s increase. Moreover, the optimal poly(2-oxazoline) EACA-POX20 significantly enhances the antibacterial activity of PMB, especially against Gram-positive ESKAPE bacteria with 16–32 folds enhancement. The combination strategy of EACA-POX20 and PMB effectively broadens the antibacterial spectrum of PMB, enabling it to combat all drug-resistant ESKAPE bacteria. This study presents a promising approach for combating ESKAPE bacteria.

摘要

临床上常用的广谱抗生素无法有效解决抗生素高度耐药ESKAPE菌感染的难题, ESKAPE耐药菌已经成为人类生命健康的重大威胁. 抗生素与佐剂的联合治疗是解决抗生素耐药菌感染的重要途径, 但是探索对所有ESKAPE耐药菌都具有广谱和高效抗菌活性的抗生素-佐剂组合仍然面临巨大挑战. 在这里, 我们提出了一种抗生素-佐剂的有效设计策略, 将对ESKAPE中耐药阴性菌具有高活性的多粘菌素B(PMB)与模拟宿主防御肽的细菌膜靶向阳离子聚(2-噁唑啉)相结合. 我们通过2-噁唑啉单体可控聚合, 合成了一系列具有不同疏水性侧链的阳离子聚(2-噁唑啉). 研究表明, 聚(2-噁唑啉)和PMB的组合效果随着聚(2-噁唑啉)侧链疏水性的提高呈现出从拮抗效应到协同效应的逐渐变化. 其中, 优选的聚(2-噁唑啉) EACA-POX20显著增强了PMB的抗菌活性, 尤其是对于ESKAPE耐药阳性菌的抗菌活性增强了16–32倍. 聚(2-噁唑啉) EACA-POX20有效增强了PMB的抗菌活性并扩展了PMB的抗菌谱. 聚(2-噁唑啉)和PMB的组合策略能够有效对抗所有耐药ESKAPE病原体, 为解决ESKAPE耐药菌提供了新的思路.

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References

  1. Larsson DGJ, Flach CF. Antibiotic resistance in the environment. Nat Rev Microbiol, 2021, 20: 257–269

    PubMed  PubMed Central  Google Scholar 

  2. Zhang D, Qian Y, Zhang S, et al. Alpha-beta chimeric polypeptide molecular brushes display potent activity against superbugs-methicillin resistant Staphylococcus aureus. Sci China Mater, 2018, 62: 604–610

    Google Scholar 

  3. Sun J, Ma X, Li R, et al. Antimicrobial nanostructured assemblies with extremely low toxicity and potent activity to eradicate Staphylococcus aureus biofilms. Small, 2023, 19: 2204039

    CAS  Google Scholar 

  4. Zhou W, Jiang X, Zhen X. Development of organic photosensitizers for antimicrobial photodynamic therapy. BioMater Sci, 2023, 11: 5108–5128

    CAS  PubMed  Google Scholar 

  5. De Oliveira DMP, Forde BM, Kidd TJ, et al. Antimicrobial resistance in ESKAPE pathogens. Clin Microbiol Rev, 2020, 33: e00181–19

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Tommasi R, Brown DG, Walkup GK, et al. Erratum: ESKAPEing the labyrinth of antibacterial discovery. Nat Rev Drug Discov, 2015, 14: 662

    CAS  Google Scholar 

  7. Wiman E, Zattarin E, Aili D, et al. Development of novel broad-spectrum antimicrobial lipopeptides derived from plantaricin NC8 β. Sci Rep, 2023, 13: 4104

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ghosh C, Sarkar P, Issa R, et al. Alternatives to conventional antibiotics in the era of antimicrobial resistance. Trends Microbiol, 2019, 27: 323–338

    CAS  PubMed  Google Scholar 

  9. Duan S, Wu R, Xiong YH, et al. Multifunctional antimicrobial materials: From rational design to biomedical applications. Prog Mater Sci, 2022, 125: 100887

    CAS  Google Scholar 

  10. Ji S, Zhou S, Zhang X, et al. An oxygen-sensitive probe and a hydrogel for optical imaging and photodynamic antimicrobial chemotherapy of chronic wounds. BioMater Sci, 2022, 10: 2054–2061

    CAS  PubMed  Google Scholar 

  11. Zhang X, Qi S, Duan X, et al. Clinical outcomes and safety of polymyxin B in the treatment of carbapenem-resistant Gram-negative bacterial infections: A real-world multicenter study. J Transl Med, 2021, 19: 431

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Trimble MJ, Mlynárčik P, Kolář M, et al. Polymyxin: Alternative mechanisms of action and resistance. Cold Spring Harb Perspect Med, 2016, 6: a025288

    PubMed  PubMed Central  Google Scholar 

  13. Mohapatra SS, Dwibedy SK, Padhy I. Polymyxins, the last-resort antibiotics: Mode of action, resistance emergence, and potential solutions. J Biosci, 2021, 46: 85

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Velkov T, Thompson PE, Nation RL, et al. Structure-activity relationships of polymyxin antibiotics. J Med Chem, 2009, 53: 1898–1916

    Google Scholar 

  15. Yin J, Meng Q, Cheng D, et al. Mechanisms of bactericidal action and resistance of polymyxins for Gram-positive bacteria. Appl Microbiol Biotechnol, 2020, 104: 3771–3780

    CAS  PubMed  Google Scholar 

  16. Vinci MC, Vattimo MdFF, Watanabe M, et al. Polymyxin B nephrotoxicity: From organ to cell damage. PLoS One, 2016, 11: e0161057

    Google Scholar 

  17. Moubareck CA. Polymyxins and bacterial membranes: A review of antibacterial activity and mechanisms of resistance. Membranes, 2020, 10: 181

    CAS  Google Scholar 

  18. Li Y, Deng Y, Zhu ZY, et al. Population pharmacokinetics of polymyxin B and dosage optimization in renal transplant patients. Front Pharmacol, 2021, 12: 727170

    PubMed  PubMed Central  Google Scholar 

  19. Kelesidis T, Falagas ME. The safety of polymyxin antibiotics. Expert Opin Drug Saf, 2015, 14: 1687–1701

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Su M, Wang M, Hong Y, et al. Polymyxin derivatives as broad-spectrum antibiotic agents. Chem Commun, 2019, 55: 13104–13107

    CAS  Google Scholar 

  21. Ekladious I, Colson YL, Grinstaff MW. Polymer–drug conjugate therapeutics: Advances, insights and prospects. Nat Rev Drug Discov, 2019, 18: 273–294

    CAS  PubMed  Google Scholar 

  22. Dhanda G, Acharya Y, Haldar J. Antibiotic adjuvants: A versatile approach to combat antibiotic resistance. ACS Omega, 2023, 8: 10757–10783

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Chen C, Shi J, Wang D, et al. Antimicrobial peptides as promising antibiotic adjuvants to combat drug-resistant pathogens. Crit Rev Microbiol, 2023, 1–18

  24. Mu S, Zhu Y, Wang Y, et al. Cationic polysaccharide conjugates as antibiotic adjuvants resensitize multidrug-resistant bacteria and prevent resistance. Adv Mater, 2022, 34: 2204065

    CAS  Google Scholar 

  25. Romanovska A, Keil J, Tophoven J, et al. Conjugates of ciprofloxacin and amphiphilic block copoly(2-alkyl-2-oxazolines)s overcome efflux pumps and are active against CIP-resistant bacteria. Mol Pharm, 2021, 18: 3532–3543

    CAS  PubMed  Google Scholar 

  26. Zhao X, Liu S, Jiang X. Leveraging bimetallic nanoparticles to synergistically enhance the efficacy of antibiotics against carbapenem-resistant bacteria. Sci China Mater, 2023, 66: 2885–2892

    CAS  Google Scholar 

  27. Ding X, Yang C, Moreira W, et al. A macromolecule reversing antibiotic resistance phenotype and repurposing drugs as potent antibiotics. Adv Sci, 2020, 7: 2001374

    CAS  Google Scholar 

  28. Liu Z, Zhao X, Yu B, et al. Rough carbon–iron oxide nanohybrids for near-infrared-II light-responsive synergistic antibacterial therapy. ACS Nano, 2021, 15: 7482–7490

    CAS  PubMed  Google Scholar 

  29. Bernal P, Molina-Santiago C, Daddaoua A, et al. Antibiotic adjuvants: Identification and clinical use. Microb Biotechnol, 2013, 6: 445–449

    PubMed  PubMed Central  Google Scholar 

  30. Zhao H, Zhong L, Yang C, et al. Antibiotic–polymer self-assembled nanocomplex to reverse phenotypic resistance of bacteria toward lastresort antibiotic colistin. ACS Nano, 2023, 17: 15411–15423

    CAS  PubMed  Google Scholar 

  31. Xie J, Zhou M, Qian Y, et al. Addressing MRSA infection and antibacterial resistance with peptoid polymers. Nat Commun, 2021, 12: 5898

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  32. Xiao X, Zhou M, Cong Z, et al. Controllable polymerization of N-substituted β-alanine N-thiocarboxyanhydrides for convenient synthesis of functional poly(β-peptoid)s. CCS Chem, 2023, 5: 994–1004

    CAS  Google Scholar 

  33. Yu H, Liu L, Li X, et al. Fabrication of polylysine based antibacterial coating for catheters by facile electrostatic interaction. Chem Eng J, 2019, 360: 1030–1041

    CAS  Google Scholar 

  34. Shi Z, Zhang X, Yu Z, et al. Facile synthesis of imidazolium-based block copolypeptides with excellent antimicrobial activity. Biomacromolecules, 2021, 22: 2373–2381

    CAS  PubMed  Google Scholar 

  35. Shen W, He P, Xiao C, et al. From antimicrobial peptides to antimicrobial poly(α-amino acid)s. Adv Healthcare Mater, 2018, 7: 1800354

    Google Scholar 

  36. Sun J, Li M, Lin M, et al. High antibacterial activity and selectivity of the versatile polysulfoniums that combat drug resistance. Adv Mater, 2021, 33: 2104402

    CAS  Google Scholar 

  37. Teng R, Yang Y, Zhang Z, et al. In situ enzyme-induced self-assembly of antimicrobial-antioxidative peptides to promote wound healing. Adv Funct Mater, 2023, 33: 2214454

    CAS  Google Scholar 

  38. Wu Y, Zhang D, Ma P, et al. Lithium hexamethyldisilazide initiated superfast ring opening polymerization of alpha-amino acid N-carboxyanhydrides. Nat Commun, 2018, 9: 5297

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sang P, Shi Y, Huang B, et al. Sulfono-γ-AApeptides as helical mimetics: Crystal structures and applications. Acc Chem Res, 2020, 53: 2425–2442

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhou M, Zou J, Liu L, et al. Synthesis of poly-α/β-peptides with tunable sequence via the copolymerization on N-carboxyanhydride and N-thiocarboxyanhydride. iScience, 2021, 24: 103124

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhou M, Xiao X, Cong Z, et al. Water-insensitive synthesis of poly-β-peptides with defined architecture. Angew Chem Int Ed, 2020, 59: 7240–7244

    CAS  Google Scholar 

  42. Krumm C, Harmuth S, Hijazi M, et al. Antimicrobial poly(2-methyloxazoline)s with bioswitchable activity through satellite group modification. Angew Chem Int Ed, 2014, 53: 3830–3834

    CAS  Google Scholar 

  43. Dai C, Zhou M, Jiang W, et al. Breaking or following the membranetargeting mechanism: Exploring the antibacterial mechanism of host defense peptide mimicking poly(2-oxazoline)s. J Mater Sci Tech, 2020, 59: 220–226

    CAS  Google Scholar 

  44. Zhou M, Jiang W, Xie J, et al. Peptide-mimicking poly(2-oxazoline)s displaying potent antimicrobial properties. ChemMedChem, 2021, 16: 309–315

    CAS  PubMed  Google Scholar 

  45. Zhou M, Qian Y, Xie J, et al. Poly(2-oxazoline)-based functional peptide mimics: Eradicating MRSA infections and persisters while alleviating antimicrobial resistance. Angew Chem Int Ed, 2020, 59: 6412–6419

    CAS  Google Scholar 

  46. Porter EA, Wang X, Lee HS, et al. Non-haemolytic β-amino-acid oligomers. Nature, 2000, 404: 565

    ADS  CAS  PubMed  Google Scholar 

  47. Wu Y, Chen Y, Yu H, et al. Dual functional diblock amino acid copolymer displaying synergistic effect with curcumin against MRSA and encapsulation of curcumin. Chin J Chem, 2023, 41: 3333–3338

    CAS  Google Scholar 

  48. Li Y, Guo S, Li X, et al. Evaluation of the in vitro synergy of polymyxin B-based combinations against polymyxin B-resistant gram-negative bacilli. Microb Pathog, 2022, 166: 105517

    CAS  PubMed  Google Scholar 

  49. Xiao X, Zhang S, Chen S, et al. An alpha/beta chimeric peptide molecular brush for eradicating MRSA biofilms and persister cells to mitigate antimicrobial resistance. BioMater Sci, 2020, 8: 6883–6889

    CAS  PubMed  Google Scholar 

  50. Yasir M, Dutta D, Willcox MDP. Comparative mode of action of the antimicrobial peptide melimine and its derivative Mel4 against Pseudomonas aeruginosa. Sci Rep, 2019, 9: 7063

    ADS  PubMed  PubMed Central  Google Scholar 

  51. Sohlenkamp C, Geiger O, Narberhaus F. Bacterial membrane lipids: Diversity in structures and pathways. FEMS Microbiol Rev, 2016, 40: 133–159

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Key Research and Development Program of China (2022YFC2303100), the National Natural Science Foundation of China (T2325010, 22305082, 52203162, and 22075078), Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism (Shanghai Municipal Education Commission), the Program of Shanghai Academic/Technology Research Leader (20XD1421400), the Open Research Fund of the State Key Laboratory of Polymer Physics and Chemistry (Changchun Institute of Applied Chemistry, Chinese Academy of Sciences), the Open Project of Engineering Research Center of Dairy Quality and Safety Control Technology (Ministry of Education, R202201), China National Postdoctoral Program for Innovative Talents (BX2021102), and China Postdoctoral Science Foundation (2022M710050). The authors also thank the Research Center of Analysis and Test of East China University of Science and Technology for the help on the characterization. Thanks for the support of the Analysis and Testing Center of School of Chemical Engineering, East China university of Science and Technology.

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Authors and Affiliations

  1. State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China

    Zhengjie Luo  (罗政杰), Min Zhou  (周敏) & Runhui Liu  (刘润辉)

  2. Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Research Center for Biomedical Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, 200237, China

    Xuebin Zhao  (赵学斌), Min Zhou  (周敏), Jingcheng Zou  (邹景橙), Ximian Xiao  (肖希勉), Longqiang Liu  (刘龙强), Jiayang Xie  (谢佳洋), Yueming Wu  (武月铭) & Runhui Liu  (刘润辉)

  3. Department of Orthopedic Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200080, China

    Wenjing Zhang  (张雯静)

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  1. Zhengjie Luo  (罗政杰)
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  9. Wenjing Zhang  (张雯静)
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  10. Runhui Liu  (刘润辉)
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Contributions

Author contributions Liu R directed the whole project. Zhou M and Liu R conceived the idea, proposed the strategy, designed the experiments, evaluated the data and wrote the manuscript together. Luo Z performed a majority of the experiments and contributed to the writing. Zhao X contributed to the antibacterial assay. Zou J conducted the SEM characterization. Xiao X, Liu L, Xie J, and Wu Y contributed to the analysis and discussion. Zhang W conducted cytotoxicity assays. All authors proofread the manuscript.

Corresponding authors

Correspondence to Min Zhou  (周敏) or Runhui Liu  (刘润辉).

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Conflict of interest The authors declare that they have no conflict of interest.

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Supplementary information Supporting data are available in the online version of the paper.

Zhengjie Luo is pursuing a Master degree majored in material science and engineering from the East China University of Science and Technology (ECUST), under the supervision of Prof. Runhui Liu. His research focuses on polymeric antimicrobial materials.

Min Zhou received his PhD degree from ECUST in 2021. He is now a postdoctoral fellow in Prof. Runhui Liu’s group at ECUST. His current research interests focus on antimicrobial polymer biomaterials.

Runhui Liu obtained a PhD degree in organic chemistry in 2009 from Purdue University. Afterward, he took postdoctoral trainings at California Institute of Technology and University of Wisconsin-Madison during 2010–2014. At the end of 2014, he took a professor position at the School of Materials Science and Engineering, ECUST. His current research focuses on the peptide polymer-based biomaterials for antimicrobial and tissue engineering applications.

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Luo, Z., Zhao, X., Zhou, M. et al. Peptide-mimicking poly(2-oxazoline)s as adjuvants to enhance activities and antibacterial spectrum of polymyxin B. Sci. China Mater. 67, 991–999 (2024). https://doi.org/10.1007/s40843-023-2744-x

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