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A potent antibiotic-loaded bone-cement implant against staphylococcal bone infections

Nature Biomedical Engineering volume 6, pages 1180–1195 (2022)Cite this article

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Abstract

New antibiotics should ideally exhibit activity against drug-resistant bacteria, delay the development of bacterial resistance to them and be suitable for local delivery at desired sites of infection. Here, we report the rational design, via molecular-docking simulations, of a library of 17 candidate antibiotics against bone infection by wild-type and mutated bacterial targets. We screened this library for activity against multidrug-resistant clinical isolates and identified an antibiotic that exhibits potent activity against resistant strains and the formation of biofilms, decreases the chances of bacterial resistance and is compatible with local delivery via a bone-cement matrix. The antibiotic-loaded bone cement exhibited greater efficacy than currently used antibiotic-loaded bone cements against staphylococcal bone infections in rats. Potent and locally delivered antibiotic-eluting polymers may help address antimicrobial resistance.

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Fig. 1: Design and in silico screening of a library of next-generation antibiotics.
Fig. 2: In vitro efficacy against clinical isolates of sensitive and resistant bacterial strains.
Fig. 3: VCD-077 retards resistance development.
Fig. 4: Antibiofilm activity of VCD-077.
Fig. 5: Physicochemical characterization of PMMA-loaded beads and cylinders.
Fig. 6: VCD-077-embedded bone-cement beads are effective against bone infections.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are available for research purposes from the corresponding authors on reasonable request. Source data for the figures are provided with this paper.

References

  1. Morris, K. Battle against antibiotic resistance is being lost. Lancet Infect. Dis. 7, 509 (2007).

    Article  Google Scholar 

  2. Bush, K. et al. Tackling antibiotic resistance. Nat. Rev. Microbiol. 9, 894–896 (2011).

    Article  CAS  Google Scholar 

  3. Teillant, A., Gandra, S., Barter, D., Morgan, D. J. & Laxminarayan, R. Potential burden of antibiotic resistance on surgery and cancer chemotherapy antibiotic prophylaxis in the USA: a literature review and modelling study. Lancet Infect. Dis. 15, 1429–1437 (2015).

    Article  Google Scholar 

  4. Willyard, C. The drug-resistant bacteria that pose the greatest health threats. Nature 543, 15 (2017).

    Article  CAS  Google Scholar 

  5. Wanted: a reward for antibiotic development. Nat. Biotechnol. 36, 555, (2018).

  6. Doron, S. & Davidson, L. E. Antimicrobial stewardship. Mayo Clin. Proc. 86, 1113–1123 (2011).

    Article  Google Scholar 

  7. Trampuz, A. & Widmer, A. F. Infections associated with orthopedic implants. Curr. Opin. Infect. Dis. 19, 349–356 (2006).

    Article  CAS  Google Scholar 

  8. Sloan, M., Premkumar, A. & Sheth, N. P. Projected volume of primary total joint arthroplasty in the U.S., 2014 to 2030. J. Bone Jt. Surg. Am. 100, 1455–1460 (2018).

    Article  Google Scholar 

  9. Moriarty, T. F. et al. Orthopaedic device-related infection: current and future interventions for improved prevention and treatment. EFORT Open Rev. 1, 89–99 (2016).

    Article  Google Scholar 

  10. Li, B. & Webster, T. J. Bacteria antibiotic resistance: new challenges and opportunities for implant-associated orthopedic infections. J. Orthop. Res. 36, 22–32 (2018).

    PubMed  Google Scholar 

  11. Arciola, C. R., Campoccia, D. & Montanaro, L. Implant infections: adhesion, biofilm formation and immune evasion. Nat. Rev. Microbiol.16, 397–409 (2018).

    Article  CAS  Google Scholar 

  12. Gogia, J. S., Meehan, J. P., Di Cesare, P. E. & Jamali, A. A. Local antibiotic therapy in osteomyelitis. Semin. Plast. Surg. 23, 100–107 (2009).

    Article  Google Scholar 

  13. Wright, J. A. & Nair, S. P. Interaction of staphylococci with bone. Int. J. Med. Microbiol. 300, 193–204 (2010).

    Article  CAS  Google Scholar 

  14. Suhardi, V. J. et al. A fully functional drug-eluting joint implant. Nat. Biomed. Eng. 1, 0080 (2017).

    Article  CAS  Google Scholar 

  15. Dowding, J. E. Mechanisms of gentamicin resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 11, 47–50 (1977).

    Article  CAS  Google Scholar 

  16. Gardete, S. & Tomasz, A. Mechanisms of vancomycin resistance in Staphylococcus aureus. J. Clin. Invest. 124, 2836–2840 (2014).

    Article  Google Scholar 

  17. Landersdorfer, C. B. et al. Pharmacokinetics and Pharmacodynamics of Antibiotics in Bone. In Bone and Joint Infections (Ed. Zimmerli, W.) 81–98 (Wiley, 2021).

  18. Hooper, D. C. Mode of action of fluoroquinolones. Drugs 58, 6–10 (1999).

    Article  CAS  Google Scholar 

  19. Acar, J. F. & Goldstein, F. W. Trends in bacterial resistance to fluoroquinolones. Clin. Infect. Dis. 24, S67–S73 (1997).

    Article  CAS  Google Scholar 

  20. Kampranis, S. C. & Maxwell, A. The DNA gyrase-quinolone complex. ATP hydrolysis and the mechanism of DNA cleavage. J. Biol. Chem. 273, 22615–22626 (1998).

    Article  CAS  Google Scholar 

  21. Aldred, K. J., Kerns, R. J. & Osheroff, N. Mechanism of quinolone action and resistance. Biochemistry 53, 1565–1574 (2014).

    Article  CAS  Google Scholar 

  22. Hooper, D. C. & Jacoby, G. A. Mechanisms of drug resistance: quinolone resistance. Ann. N. Y. Acad. Sci. 1354, 12–31 (2015).

    Article  CAS  Google Scholar 

  23. Blower, T. R., Williamson, B. H., Kerns, R. J. & Berger, J. M. Crystal structure and stability of gyrase–fluoroquinolone cleaved complexes from Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 113, 1706–1713 (2016).

    Article  CAS  Google Scholar 

  24. Conrad, S. et al. gyrA mutations in high-level fluoroquinolone-resistant clinical isolates of Escherichia coli. J. Antimicrob. Chemother. 38, 443–455 (1996).

    Article  CAS  Google Scholar 

  25. Chan, P. F. et al. Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin. Nat. Commun. 6, 10048 (2015).

  26. Diekema, D. J. et al. Survey of infections due to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997–1999. Clin. Infect. Dis. 32, S114–S132 (2001).

    Article  CAS  Google Scholar 

  27. Zimmerli, W. Clinical presentation and treatment of orthopaedic implant-associated infection. J. Intern. Med. 276, 111–119 (2014).

    Article  CAS  Google Scholar 

  28. Kim, W. et al. A new class of synthetic retinoid antibiotics effective against bacterial persisters. Nature 556, 103–107 (2018).

    Article  CAS  Google Scholar 

  29. Peeters, E. et al. Modulation of the substitution pattern of 5-aryl-2-aminoimidazoles allows fine-tuning of their antibiofilm activity spectrum and toxicity. Antimicrob. Agents Chemother. 60, 6483–6497 (2016).

    Article  CAS  Google Scholar 

  30. Cramariuc, O. et al. Mechanism for translocation of fluoroquinolones across lipid membranes. Biochim. Biophys. Acta 1818, 2563–2571 (2012).

    Article  CAS  Google Scholar 

  31. Vroom, J. M. et al. Depth penetration and detection of pH gradients in biofilms by two-photon excitation microscopy. Appl. Environ. Microbiol. 65, 3502–3511 (1999).

    Article  CAS  Google Scholar 

  32. Lebeaux, D., Leflon-Guibout, V., Ghigo, J. M. & Beloin, C. In vitro activity of gentamicin, vancomycin or amikacin combined with EDTA or l-arginine as lock therapy against a wide spectrum of biofilm-forming clinical strains isolated from catheter-related infections. J. Antimicrob. Chemother. 70, 1704–1712 (2015).

    Article  CAS  Google Scholar 

  33. McMahon. S. et al. Thermal necrosis and PMMA – a cause for concern? Orthop. Proc. 94-B, 64 (2012).

  34. Hussain, S. et al. Antibiotic-loaded nanoparticles targeted to the site of infection enhance antibacterial efficacy. Nat. Biomed. Eng. 2, 95–103 (2018).

    Article  CAS  Google Scholar 

  35. ASTM Standard, ASTM F451. in Annual Book of ASTM Standards Vol. 13.01 55–61 (ASTM International, 2000). https://www.astm.org

  36. Kurtz, S., Ong, K., Lau, E., Mowat, F. & Halpern, M. Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J. Bone Jt. Surg. Am. 89, 780–785 (2007).

    Article  Google Scholar 

  37. Bryan, A. J. et al. Irrigation and debridement with component retention for acute infection after hip arthroplasty: improved results with contemporary management. J. Bone Jt. Surg. Am. 99, 2011–2018 (2017).

    Article  Google Scholar 

  38. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/early-development-considerations-innovative-combination-products (US FDA, 2020).

  39. Bistolfi, A., Ferracini, R., Albanese, C., Vernè, E. & Miola, M. PMMA-based bone cements and the problem of joint arthroplasty infections: status and new perspectives. Materials 12, 4002 (2019).

    Article  CAS  Google Scholar 

  40. Stokes, J. M. et al. A deep learning approach to antibiotic discovery. Cell 181, 475–483 (2020).

    Article  CAS  Google Scholar 

  41. FDA. (ed https://www.fda.gov/regulatory-information/search-fda-guidance-documents/principles-premarket-pathways-combination-products) (US FDA, 2022).

  42. Entenza, J. M., Giddey, M., Vouillamoz, J. & Moreillon, P. In vitro prevention of the emergence of daptomycin resistance in Staphylococcus aureus and enterococci following combination with amoxicillin/clavulanic acid or ampicillin. Int. J. Antimicrob. Agents 35, 451–456 (2010).

    Article  CAS  Google Scholar 

  43. Metzler, K., Drlica, K. & Blondeau, J. M. Minimal inhibitory and mutant prevention concentrations of azithromycin, clarithromycin and erythromycin for clinical isolates of Streptococcus pneumoniae. J. Antimicrob. Chemother. 68, 631–635 (2013).

    Article  CAS  Google Scholar 

  44. Guy, R. H. H. & On, J. The determination of drug release rates from topical dosage forms. Int. J. Pharm. 60, R1–R3 (1990).

    Article  CAS  Google Scholar 

  45. Rissing, J. P., Buxton, T. B., Weinstein, R. S. & Shockley, R. K. Model of experimental chronic osteomyelitis in rats. Infect. Immun. 47, 581–586 (1985).

    Article  CAS  Google Scholar 

  46. Rouse, M. S. et al. Daptomycin treatment of Staphylococcus aureus experimental chronic osteomyelitis. J. Antimicrob. Chemother. 57, 301–305 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Bandopadhayaya for his dedication in providing us with clinical perspectives and detailed explanations while conceiving the project. The authors from Vyome Therapeutics Limited acknowledge the funding support from the Biotechnology Industry Research Assistance Council, Department of Biotechnology (DBT), India, under a Small Business Innovation Research Initiative grant. H.L.J. discloses support for the publication of this study from the National Institutes of Health (grant numbers AR073135 and CA236702) and the Department of Defense (grant numbers PC180355 and CA201065).

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Author notes

  1. These authors contributed equally: Sumana Ghosh, Mau Sinha.

Authors and Affiliations

  1. Vyome Therapeutics Inc., Princeton, NJ, USA

    Sumana Ghosh, Mau Sinha, Ritwik Samanta, Suresh Sadhasivam, Anamika Bhattacharyya, Ashis Nandy, Swamini Saini, Nupur Tandon, Himanshi Singh, Swati Gupta, Anjali Chauhan, Keerthi Kumar Aavula, Mukesh Kumar Garg & Shamik Ghosh

  2. Vyome Therapeutics Limited, New Delhi, India

    Sumana Ghosh, Mau Sinha, Ritwik Samanta, Suresh Sadhasivam, Anamika Bhattacharyya, Ashis Nandy, Swamini Saini, Nupur Tandon, Himanshi Singh, Swati Gupta, Anjali Chauhan, Keerthi Kumar Aavula, Mukesh Kumar Garg & Shamik Ghosh

  3. Department of Biotechnology, Indian Institute of Technology, Kharagpur, India

    Sneha Susan Varghese & Sudip Ghosh

  4. Center for Engineered Therapeutics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Pujie Shi, Tanmoy Saha, Aparna Padhye, Hae Lin Jang & Shiladitya Sengupta

  5. Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA

    Pujie Shi, Tanmoy Saha, Aparna Padhye & Shiladitya Sengupta

  6. Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Pujie Shi, Aparna Padhye & Hae Lin Jang

  7. Department of Orthopedic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Pujie Shi, Aparna Padhye & Hae Lin Jang

Authors
  1. Sumana Ghosh
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Contributions

Sumana Ghosh and M.S. designed and performed the experiments, and contributed to the analysis of the results and the writing of the manuscript. R.S., S. Sadhasivam, A.B., A.N., S. Saini, N.T., H.S., S. Gupta, A.C., K.K.A., S.S.V., P.S., M.K.G., T.S. and A.P. contributed to the design and experimentation, and to the analysis of the results. Sudip Ghosh provided resources. Shamik Ghosh, H.L.J. and S. Sengupta designed and supervised the study, and contributed to the analysis of the results and the writing of the paper.

Corresponding authors

Correspondence to Shamik Ghosh, Hae Lin Jang or Shiladitya Sengupta.

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Competing interests

Sumana Ghosh, M.S., R.S., S. Sadhasivam, A.N., A.B., S. Saini, N.T., H.S., S. Gupta, A.C., M.K.G. and Shamik Ghosh are employees of Vyome Therapeutics Limited. Sumana Ghosh and Shamik Ghosh hold equity in Vyome Therapeutics Inc. S. Sengupta is a co-founder and board member of Vyome Therapeutics Limited, and owns equity in Vyome Therapeutics Inc. H.L.J. is a founder of Curer Inc. and holds equity in the company. S.S.V. and Sudip Ghosh declare no competing interests.

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Extended data

Extended Data Fig. 1 Physicochemical characterization of VCD-077 impregnated PMMA beads.

(a-c) FT-IR spectrum of different groups (a) VCD-077, (b) PMMA, (c) VCD-077 impregnated PMMA at (40:1) with VCD-077 peaks 1 (3352.75 cm−1), 2 (3114.27 cm−1), 3 (1643.82 cm−1), 4 (1615.48 cm−1), 5 (1595.79 cm−1), 6 (1550.68 cm−1), 7 (1352.31 cm−1), 8 (1313.02 cm−1).(d) Release of VCD-077 from Smartset HV® (PMMA) bead at different drug:polymer ratio (1:40, 2:40 and 3:40) in pH 7.4 buffer. Data is represented as mean ± SD (n = 3). (e) Release of VCD-077 from Smartset HV® (PMMA) bead at different particle size from drug:polymer ratio (1:40) or (f) at different temperatures, in pH 7.4 buffer. Data is represented as mean ± SD (n = 3).

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Ghosh, S., Sinha, M., Samanta, R. et al. A potent antibiotic-loaded bone-cement implant against staphylococcal bone infections. Nat. Biomed. Eng 6, 1180–1195 (2022). https://doi.org/10.1038/s41551-022-00950-x

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