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

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support SIMILAR CONTENT BEING VIEWED BY OTHERS EVIDENCE OF BISPHOSPHONATE-CONJUGATED SITAFLOXACIN ERADICATION OF ESTABLISHED METHICILLIN-RESISTANT _S. AUREUS_ INFECTION WITH

OSSEOINTEGRATION IN MURINE MODELS OF IMPLANT-ASSOCIATED OSTEOMYELITIS Article Open access 18 October 2023 COMBINATION OF BACTERIOPHAGES AND VANCOMYCIN IN A CO-DELIVERY HYDROGEL FOR LOCALIZED

TREATMENT OF FRACTURE-RELATED INFECTIONS Article Open access 29 August 2024 EVALUATION OF A BONE FILLER SCAFFOLD FOR LOCAL ANTIBIOTIC DELIVERY TO PREVENT _STAPHYLOCOCCUS AUREUS_ INFECTION

IN A CONTAMINATED BONE DEFECT Article Open access 13 May 2021 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

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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). AUTHOR INFORMATION Author notes * These authors contributed equally: Sumana Ghosh, Mau Sinha. AUTHORS AND AFFILIATIONS * 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 * 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 * Department of

Biotechnology, Indian Institute of Technology, Kharagpur, India Sneha Susan Varghese & Sudip Ghosh * 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 * Harvard-MIT Division of Health Sciences and Technology,

Cambridge, MA, USA Pujie Shi, Tanmoy Saha, Aparna Padhye & Shiladitya Sengupta * 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 * Department of Orthopedic Surgery, Brigham and Women’s Hospital, Harvard Medical School,

Boston, MA, USA Pujie Shi, Aparna Padhye & Hae Lin Jang Authors * Sumana Ghosh View author publications You can also search for this author inPubMed Google Scholar * Mau Sinha View

author publications You can also search for this author inPubMed Google Scholar * Ritwik Samanta View author publications You can also search for this author inPubMed Google Scholar * Suresh

Sadhasivam View author publications You can also search for this author inPubMed Google Scholar * Anamika Bhattacharyya View author publications You can also search for this author inPubMed

 Google Scholar * Ashis Nandy View author publications You can also search for this author inPubMed Google Scholar * Swamini Saini View author publications You can also search for this

author inPubMed Google Scholar * Nupur Tandon View author publications You can also search for this author inPubMed Google Scholar * Himanshi Singh View author publications You can also

search for this author inPubMed Google Scholar * Swati Gupta View author publications You can also search for this author inPubMed Google Scholar * Anjali Chauhan View author publications

You can also search for this author inPubMed Google Scholar * Keerthi Kumar Aavula View author publications You can also search for this author inPubMed Google Scholar * Sneha Susan Varghese

View author publications You can also search for this author inPubMed Google Scholar * Pujie Shi View author publications You can also search for this author inPubMed Google Scholar * Sudip

Ghosh View author publications You can also search for this author inPubMed Google Scholar * Mukesh Kumar Garg View author publications You can also search for this author inPubMed Google

Scholar * Tanmoy Saha View author publications You can also search for this author inPubMed Google Scholar * Aparna Padhye View author publications You can also search for this author

inPubMed Google Scholar * Shamik Ghosh View author publications You can also search for this author inPubMed Google Scholar * Hae Lin Jang View author publications You can also search for

this author inPubMed Google Scholar * Shiladitya Sengupta View author publications You can also search for this author inPubMed Google Scholar 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. ETHICS DECLARATIONS 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. PEER REVIEW PEER REVIEW

INFORMATION _Nature Biomedical Engineering_ thanks Ebru Oral, Liam Grover and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. ADDITIONAL INFORMATION

PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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). Source data SUPPLEMENTARY INFORMATION MAIN SUPPLEMENTARY

INFORMATION Supplementary figures, tables and methods. REPORTING SUMMARY SOURCE DATA SOURCE DATA FOR FIGS. 3, 5, 6 AND EXTENDED DATA FIG. 1 Source data. RIGHTS AND PERMISSIONS Springer

Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript

version of this article is solely governed by the terms of such publishing agreement and applicable law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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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