Role of antibiotic delivery system targeting bacterial biofilm based on ε-poly-<i>L</i>-lysine and cyclodextrin in treatment of bone and joint infections_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

LIU Tiexin ^1,2 , LIN Junqing ^1,2 ,  ZHENG Xianyou ^1,2

1. Department of Orthopedics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, P. R. China;
2. National Orthopedic Medical Center, Shanghai, 200233, P. R. China;

Corresponding author：

ZHENG Xianyou, Email: zhengxianyou@126.com

Keywords：

Bone and joint infections; ε-poly-L-lysine; cyclodextrin; antibiotic delivery; biofilm; rat

DOI：

10.7507/1002-1892.202412031

Video：

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Objective To explore the mechanism of antibiotic delivery system targeting bacterial biofilm with linezolid (LZD) based on ε-poly-L-lysine (ε-PLL) and cyclodextrin (CD) (ε-PLL-CD-LZD), aiming to enhance antibiotic bioavailability, effectively penetrate and disrupt biofilm structures, and thereby improve the treatment of bone and joint infections. Methods ε-PLL-CD-LZD was synthesized via chemical methods. The grafting rate of CD was characterized using nuclear magnetic resonance. In vitro biocompatibility was evaluated through live/dead cell staining after co-culturing with mouse embryonic osteoblast precursor cells (MC3T3-E1), human umbilical vein endothelial cells, and mouse embryonic fibroblast cells (3T3-L1). The biofilm-enrichment capacity of ε-PLL-CD-LZD was assessed using Staphylococcus aureus biofilms through enrichment studies. Its biofilm eradication efficacy was investigated via minimum inhibitory concentration (MIC) determination, scanning electron microscopy, and live/dead bacterial staining. A bone and joint infection model in male Sprague-Dawley rats was established to validate the antibacterial effects of ε-PLL-CD-LZD. Results In ε-PLL-CD-LZD, the average grafting rate of CD reached 9.88%. The cell viability exceeded 90% after co-culture with three types cells. The strong biofilm enrichment capability was observed with a MIC of 2 mg/L. Scanning electron microscopy observations revealed the effective disruption of biofilm structure, indicating potent biofilm eradication capacity. In vivo rat experiments demonstrated that ε-PLL-CD-LZD significantly reduced bacterial load and infection positivity rate at the lesion site (P<0.05). Conclusion The ε-PLL-CD antibiotic delivery system provides a treatment strategy for bone and joint infections with high clinical translational significance. By effectively enhancing antibiotic bioavailability, penetrating, and disrupting biofilms, it demonstrated significant anti-infection effects in animal models.

1.	Hardy C, Osei L, Basset T, et al. Bone and joint infections with Staphylococcus aureus strains producing Panton-Valentine Leukocidin in French Guiana. Medicine (Baltimore), 2019, 98(27): e16015. doi: 10.1097/MD.0000000000016015.
2.	Laurent E, Gras G, Druon J, et al. Key features of bone and joint infections following the implementation of reference centers in France. Med Mal Infect, 2018, 48(4): 256-262.
3.	Tanaka-Azevedo AM, Torquato RJ, Tanaka AS, et al. Characterization of Bothrops jararaca coagulation inhibitor (BJI) and presence of similar protein in plasma of other animals. Toxicon, 2004, 44(3): 289-294.
4.	Pham TT, Andrey DO, Stampf S, et al. Epidemiology and outcomes of bone and joint infections in solid organ transplant recipients. Am J Transplant, 2022, 22(12): 3031-3046.
5.	Aboelnaga N, Elsayed SW, Abdelsalam NA, et al. Deciphering the dynamics of methicillin-resistant Staphylococcus aureus biofilm formation: from molecular signaling to nanotherapeutic advances. Cell Commun Signal, 2024, 22(1): 188. doi: 10.1186/s12964-024-01511-2.
6.	Hu D, Li H, Wang B, et al. Surface-adaptive gold nanoparticles with effective adherence and enhanced photothermal ablation of methicillin-resistant Staphylococcus aureus biofilm. ACS Nano, 2017, 11(9): 9330-9339.
7.	Jiao D, Yang S. Overcoming resistance to drugs targeting KRASG12C mutation. Innovation (Camb), 2020, 1(2): 100035. doi: 10.1016/j.xinn.2020.100035.
8.	Abad L, Tafani V, Tasse J, et al. Evaluation of the ability of linezolid and tedizolid to eradicate intraosteoblastic and biofilm-embedded Staphylococcus aureus in the bone and joint infection setting. J Antimicrob Chemother, 2019, 74(3): 625-632.
9.	Ferry T. A review of phage therapy for bone and joint infections. Methods Mol Biol, 2024, 2734: 207-235.
10.	Bhattacharya M, Horswill AR. The role of human extracellular matrix proteins in defining Staphylococcus aureus biofilm infections. FEMS Microbiol Rev, 2024, 48(1): fuae002. doi: 10.1093/femsre/fuae002.
11.	丁梦, 宋凌杰, 栾世方. 载药ZIF-8对医用高分子材料表面生物膜的清除性能分析. 分析化学, 2023, 51(11): 1835-1843.
12.	Qu J, Zhao X, Liang Y, et al. Antibacterial adhesive injectable hydrogels with rapid self-healing, extensibility and compressibility as wound dressing for joints skin wound healing. Biomaterials, 2018, 183: 185-199.
13.	Sisson TL, Jungbluth GL, Hopkins NK. Age and sex effects on the pharmacokinetics of linezolid. Eur J Clin Pharmacol, 2002, 57(11): 793-797.
14.	Bankar SB, Singhal RS. Panorama of poly-ε-lysine. RSC Advances, 2013, 3(23): 8586-8603.
15.	Lin J, Hu W, Gao T, et al. ε-poly-L-lysine as an efficient cartilage penetrating and residing drug carrier with high intraarticular injection safety for treating osteoarthritis. Chemical Engineering Journal, 2022, 430(3): 133018. doi: 10.1016/j.cej.2021.133018.
16.	Yao Q, Huang ZW, Zhai YY, et al. Localized controlled release of bilirubin from β-cyclodextrin-conjugated ε-polylysine to attenuate oxidative stress and inflammation in transplanted islets. ACS Appl Mater Interfaces, 2020, 12(5): 5462-5475.
17.	Natesan S, Sowrirajan C, Yousuf S, et al. Mode of encapsulation of linezolid by β-cyclodextrin and its role in bovine serum albumin binding. Carbohydr Polym, 2015, 115: 589-597.
18.	Wu J, Shen P, Qin X, et al. Self-supply of H₂O₂ and O₂ by a composite nanogenerator for chemodynamic therapy/hypoxia improvement and rapid therapy of biofilm-infected wounds. Chemical Engineering Journal, 2023. https://doi.org/10.1016/j.cej.2023.141507.
19.	Lin J, Gao T, Wei H, et al. Optimal concentration of ethylenediaminetetraacetic acid as an irrigation solution additive to reduce infection rates in rat models of contaminated wound. Bone Joint Res, 2021, 10(1): 68-76.
20.	Lin J, Suo J, Bao B, et al. Efficacy of EDTA-NS irrigation in eradicating Staphylococcus aureus biofilm-associated infection. Bone Joint Res, 2024, 13(1): 40-51.
21.	Smith AW. Biofilms and antibiotic therapy: is there a role for combating bacterial resistance by the use of novel drug delivery systems? Adv Drug Deliv Rev, 2005, 57(10): 1539-1550.
22.	Kolpen M, Lerche CJ, Kragh KN, et al. Hyperbaric oxygen sensitizes anoxic pseudomonas aeruginosa biofilm to ciprofloxacin. Antimicrob Agents Chemother, 2017, 61(11): e01024-e01017.
23.	Xiu W, Wan L, Yang K, et al. Potentiating hypoxic microenvironment for antibiotic activation by photodynamic therapy to combat bacterial biofilm infections. Nat Commun, 2022, 13(1): 3875. doi: 10.1038/s41467-022-31479-x.
24.	Abad L, Josse J, Tasse J, et al. Antibiofilm and intraosteoblastic activities of rifamycins against Staphylococcus aureus: promising in vitro profile of rifabutin. J Antimicrob Chemother, 2020, 75(6): 1466-1473.
25.	Dupieux C, Trouillet-Assant S, Camus C, et al. Intraosteoblastic activity of daptomycin in combination with oxacillin and ceftaroline against MSSA and MRSA. J Antimicrob Chemother, 2017, 72(12): 3353-3356.
26.	Klein S, Nurjadi D, Eigenbrod T, et al. Evaluation of antibiotic resistance to orally administrable antibiotics in staphylococcal bone and joint infections in one of the largest university hospitals in Germany: is there a role for fusidic acid? Int J Antimicrob Agents, 2016, 47(2): 155-157.
27.	Valour F, Trouillet-Assant S, Riffard N, et al. Antimicrobial activity against intraosteoblastic Staphylococcus aureus. Antimicrob Agents Chemother, 2015, 59(4): 2029-2036.
28.	Modi SK, Gaur S, Sengupta M, et al. Mechanistic insights into nanoparticle surface-bacterial membrane interactions in overcoming antibiotic resistance. Front Microbiol, 2023, 14: 1135579. doi: 10.3389/fmicb.2023.1135579.

1. Hardy C, Osei L, Basset T, et al. Bone and joint infections with Staphylococcus aureus strains producing Panton-Valentine Leukocidin in French Guiana. Medicine (Baltimore), 2019, 98(27): e16015. doi: 10.1097/MD.0000000000016015.
2. Laurent E, Gras G, Druon J, et al. Key features of bone and joint infections following the implementation of reference centers in France. Med Mal Infect, 2018, 48(4): 256-262.
3. Tanaka-Azevedo AM, Torquato RJ, Tanaka AS, et al. Characterization of Bothrops jararaca coagulation inhibitor (BJI) and presence of similar protein in plasma of other animals. Toxicon, 2004, 44(3): 289-294.
4. Pham TT, Andrey DO, Stampf S, et al. Epidemiology and outcomes of bone and joint infections in solid organ transplant recipients. Am J Transplant, 2022, 22(12): 3031-3046.
5. Aboelnaga N, Elsayed SW, Abdelsalam NA, et al. Deciphering the dynamics of methicillin-resistant Staphylococcus aureus biofilm formation: from molecular signaling to nanotherapeutic advances. Cell Commun Signal, 2024, 22(1): 188. doi: 10.1186/s12964-024-01511-2.
6. Hu D, Li H, Wang B, et al. Surface-adaptive gold nanoparticles with effective adherence and enhanced photothermal ablation of methicillin-resistant Staphylococcus aureus biofilm. ACS Nano, 2017, 11(9): 9330-9339.
7. Jiao D, Yang S. Overcoming resistance to drugs targeting KRASG12C mutation. Innovation (Camb), 2020, 1(2): 100035. doi: 10.1016/j.xinn.2020.100035.
8. Abad L, Tafani V, Tasse J, et al. Evaluation of the ability of linezolid and tedizolid to eradicate intraosteoblastic and biofilm-embedded Staphylococcus aureus in the bone and joint infection setting. J Antimicrob Chemother, 2019, 74(3): 625-632.
9. Ferry T. A review of phage therapy for bone and joint infections. Methods Mol Biol, 2024, 2734: 207-235.
10. Bhattacharya M, Horswill AR. The role of human extracellular matrix proteins in defining Staphylococcus aureus biofilm infections. FEMS Microbiol Rev, 2024, 48(1): fuae002. doi: 10.1093/femsre/fuae002.
11. 丁梦, 宋凌杰, 栾世方. 载药ZIF-8对医用高分子材料表面生物膜的清除性能分析. 分析化学, 2023, 51(11): 1835-1843.
12. Qu J, Zhao X, Liang Y, et al. Antibacterial adhesive injectable hydrogels with rapid self-healing, extensibility and compressibility as wound dressing for joints skin wound healing. Biomaterials, 2018, 183: 185-199.
13. Sisson TL, Jungbluth GL, Hopkins NK. Age and sex effects on the pharmacokinetics of linezolid. Eur J Clin Pharmacol, 2002, 57(11): 793-797.
14. Bankar SB, Singhal RS. Panorama of poly-ε-lysine. RSC Advances, 2013, 3(23): 8586-8603.
15. Lin J, Hu W, Gao T, et al. ε-poly-L-lysine as an efficient cartilage penetrating and residing drug carrier with high intraarticular injection safety for treating osteoarthritis. Chemical Engineering Journal, 2022, 430(3): 133018. doi: 10.1016/j.cej.2021.133018.
16. Yao Q, Huang ZW, Zhai YY, et al. Localized controlled release of bilirubin from β-cyclodextrin-conjugated ε-polylysine to attenuate oxidative stress and inflammation in transplanted islets. ACS Appl Mater Interfaces, 2020, 12(5): 5462-5475.
17. Natesan S, Sowrirajan C, Yousuf S, et al. Mode of encapsulation of linezolid by β-cyclodextrin and its role in bovine serum albumin binding. Carbohydr Polym, 2015, 115: 589-597.
18. Wu J, Shen P, Qin X, et al. Self-supply of H₂O₂ and O₂ by a composite nanogenerator for chemodynamic therapy/hypoxia improvement and rapid therapy of biofilm-infected wounds. Chemical Engineering Journal, 2023. https://doi.org/10.1016/j.cej.2023.141507.
19. Lin J, Gao T, Wei H, et al. Optimal concentration of ethylenediaminetetraacetic acid as an irrigation solution additive to reduce infection rates in rat models of contaminated wound. Bone Joint Res, 2021, 10(1): 68-76.
20. Lin J, Suo J, Bao B, et al. Efficacy of EDTA-NS irrigation in eradicating Staphylococcus aureus biofilm-associated infection. Bone Joint Res, 2024, 13(1): 40-51.
21. Smith AW. Biofilms and antibiotic therapy: is there a role for combating bacterial resistance by the use of novel drug delivery systems? Adv Drug Deliv Rev, 2005, 57(10): 1539-1550.
22. Kolpen M, Lerche CJ, Kragh KN, et al. Hyperbaric oxygen sensitizes anoxic pseudomonas aeruginosa biofilm to ciprofloxacin. Antimicrob Agents Chemother, 2017, 61(11): e01024-e01017.
23. Xiu W, Wan L, Yang K, et al. Potentiating hypoxic microenvironment for antibiotic activation by photodynamic therapy to combat bacterial biofilm infections. Nat Commun, 2022, 13(1): 3875. doi: 10.1038/s41467-022-31479-x.
24. Abad L, Josse J, Tasse J, et al. Antibiofilm and intraosteoblastic activities of rifamycins against Staphylococcus aureus: promising in vitro profile of rifabutin. J Antimicrob Chemother, 2020, 75(6): 1466-1473.
25. Dupieux C, Trouillet-Assant S, Camus C, et al. Intraosteoblastic activity of daptomycin in combination with oxacillin and ceftaroline against MSSA and MRSA. J Antimicrob Chemother, 2017, 72(12): 3353-3356.
26. Klein S, Nurjadi D, Eigenbrod T, et al. Evaluation of antibiotic resistance to orally administrable antibiotics in staphylococcal bone and joint infections in one of the largest university hospitals in Germany: is there a role for fusidic acid? Int J Antimicrob Agents, 2016, 47(2): 155-157.
27. Valour F, Trouillet-Assant S, Riffard N, et al. Antimicrobial activity against intraosteoblastic Staphylococcus aureus. Antimicrob Agents Chemother, 2015, 59(4): 2029-2036.
28. Modi SK, Gaur S, Sengupta M, et al. Mechanistic insights into nanoparticle surface-bacterial membrane interactions in overcoming antibiotic resistance. Front Microbiol, 2023, 14: 1135579. doi: 10.3389/fmicb.2023.1135579.

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