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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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.
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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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