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Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and Tedizolid
The use of local antibiotics to treat bone infections has been questioned due to a lack of clinical efficacy and emerging information about Staphylococcus aureus colonization of the osteocyte-lacuno canalicular network (OLCN). Here we propose bisphosphonate-conjugated antibiotics (BCA) using a “targ...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235690/ https://www.ncbi.nlm.nih.gov/pubmed/34204351 http://dx.doi.org/10.3390/antibiotics10060732 |
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author | Adjei-Sowah, Emmanuela Peng, Yue Weeks, Jason Jonason, Jennifer H. de Mesy Bentley, Karen L. Masters, Elysia Morita, Yugo Muthukrishnan, Gowrishankar Cherian, Philip Hu, X. Eric McKenna, Charles E. Ebetino, Frank H. Sun, Shuting Schwarz, Edward M. Xie, Chao |
author_facet | Adjei-Sowah, Emmanuela Peng, Yue Weeks, Jason Jonason, Jennifer H. de Mesy Bentley, Karen L. Masters, Elysia Morita, Yugo Muthukrishnan, Gowrishankar Cherian, Philip Hu, X. Eric McKenna, Charles E. Ebetino, Frank H. Sun, Shuting Schwarz, Edward M. Xie, Chao |
author_sort | Adjei-Sowah, Emmanuela |
collection | PubMed |
description | The use of local antibiotics to treat bone infections has been questioned due to a lack of clinical efficacy and emerging information about Staphylococcus aureus colonization of the osteocyte-lacuno canalicular network (OLCN). Here we propose bisphosphonate-conjugated antibiotics (BCA) using a “target and release” approach to deliver antibiotics to bone infection sites. A fluorescent bisphosphonate probe was used to demonstrate bone surface labeling adjacent to bacteria in a S. aureus infected mouse tibiae model. Bisphosphonate and hydroxybisphosphonate conjugates of sitafloxacin and tedizolid (BCA) were synthesized using hydroxyphenyl and aminophenyl carbamate linkers, respectively. The conjugates were adequately stable in serum. Their cytolytic activity versus parent drug on MSSA and MRSA static biofilms grown on hydroxyapatite discs was established by scanning electron microscopy. Sitafloxacin O-phenyl carbamate BCA was effective in eradicating static biofilm: no colony formation units (CFU) were recovered following treatment with 800 mg/L of either the bisphosphonate or α-hydroxybisphosphonate conjugated drug (p < 0.001). In contrast, the less labile tedizolid N-phenyl carbamate linked BCA had limited efficacy against MSSA, and MRSA. CFU were recovered from all tedizolid BCA treatments. These results demonstrate the feasibility of BCA eradication of S. aureus biofilm on OLCN bone surfaces and support in vivo drug development of a sitafloxacin BCA. |
format | Online Article Text |
id | pubmed-8235690 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-82356902021-06-27 Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and Tedizolid Adjei-Sowah, Emmanuela Peng, Yue Weeks, Jason Jonason, Jennifer H. de Mesy Bentley, Karen L. Masters, Elysia Morita, Yugo Muthukrishnan, Gowrishankar Cherian, Philip Hu, X. Eric McKenna, Charles E. Ebetino, Frank H. Sun, Shuting Schwarz, Edward M. Xie, Chao Antibiotics (Basel) Article The use of local antibiotics to treat bone infections has been questioned due to a lack of clinical efficacy and emerging information about Staphylococcus aureus colonization of the osteocyte-lacuno canalicular network (OLCN). Here we propose bisphosphonate-conjugated antibiotics (BCA) using a “target and release” approach to deliver antibiotics to bone infection sites. A fluorescent bisphosphonate probe was used to demonstrate bone surface labeling adjacent to bacteria in a S. aureus infected mouse tibiae model. Bisphosphonate and hydroxybisphosphonate conjugates of sitafloxacin and tedizolid (BCA) were synthesized using hydroxyphenyl and aminophenyl carbamate linkers, respectively. The conjugates were adequately stable in serum. Their cytolytic activity versus parent drug on MSSA and MRSA static biofilms grown on hydroxyapatite discs was established by scanning electron microscopy. Sitafloxacin O-phenyl carbamate BCA was effective in eradicating static biofilm: no colony formation units (CFU) were recovered following treatment with 800 mg/L of either the bisphosphonate or α-hydroxybisphosphonate conjugated drug (p < 0.001). In contrast, the less labile tedizolid N-phenyl carbamate linked BCA had limited efficacy against MSSA, and MRSA. CFU were recovered from all tedizolid BCA treatments. These results demonstrate the feasibility of BCA eradication of S. aureus biofilm on OLCN bone surfaces and support in vivo drug development of a sitafloxacin BCA. MDPI 2021-06-17 /pmc/articles/PMC8235690/ /pubmed/34204351 http://dx.doi.org/10.3390/antibiotics10060732 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Adjei-Sowah, Emmanuela Peng, Yue Weeks, Jason Jonason, Jennifer H. de Mesy Bentley, Karen L. Masters, Elysia Morita, Yugo Muthukrishnan, Gowrishankar Cherian, Philip Hu, X. Eric McKenna, Charles E. Ebetino, Frank H. Sun, Shuting Schwarz, Edward M. Xie, Chao Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and Tedizolid |
title | Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and Tedizolid |
title_full | Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and Tedizolid |
title_fullStr | Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and Tedizolid |
title_full_unstemmed | Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and Tedizolid |
title_short | Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and Tedizolid |
title_sort | development of bisphosphonate-conjugated antibiotics to overcome pharmacodynamic limitations of local therapy: initial results with carbamate linked sitafloxacin and tedizolid |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235690/ https://www.ncbi.nlm.nih.gov/pubmed/34204351 http://dx.doi.org/10.3390/antibiotics10060732 |
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