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

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.

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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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Authors and Affiliations

Authors

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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