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 <i>Staphylococcus aureus</i> colonization of the osteocyte-lacuno canalicular network (OLCN). Here we propose bisphosphonate-conjugated antibiotics...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-06-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/10/6/732 |
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| author | Emmanuela Adjei-Sowah Yue Peng Jason Weeks Jennifer H. Jonason Karen L. de Mesy Bentley Elysia Masters Yugo Morita Gowrishankar Muthukrishnan Philip Cherian X. Eric Hu Charles E. McKenna Frank H. Ebetino Shuting Sun Edward M. Schwarz Chao Xie |
| author_facet | Emmanuela Adjei-Sowah Yue Peng Jason Weeks Jennifer H. Jonason Karen L. de Mesy Bentley Elysia Masters Yugo Morita Gowrishankar Muthukrishnan Philip Cherian X. Eric Hu Charles E. McKenna Frank H. Ebetino Shuting Sun Edward M. Schwarz Chao Xie |
| author_sort | Emmanuela Adjei-Sowah |
| collection | DOAJ |
| description | The use of local antibiotics to treat bone infections has been questioned due to a lack of clinical efficacy and emerging information about <i>Staphylococcus aureus</i> 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 <i>S. aureus</i> 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 <i>O</i>-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 (<i>p</i> < 0.001). In contrast, the less labile tedizolid <i>N</i>-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 <i>S. aureus</i> biofilm on OLCN bone surfaces and support in vivo drug development of a sitafloxacin BCA. |
| first_indexed | 2024-03-10T10:19:27Z |
| format | Article |
| id | doaj.art-55d8be3a8e344453a7cad2e4bff9c98b |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-10T10:19:27Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-55d8be3a8e344453a7cad2e4bff9c98b2023-11-22T00:30:36ZengMDPI AGAntibiotics2079-63822021-06-0110673210.3390/antibiotics10060732Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and TedizolidEmmanuela Adjei-Sowah0Yue Peng1Jason Weeks2Jennifer H. Jonason3Karen L. de Mesy Bentley4Elysia Masters5Yugo Morita6Gowrishankar Muthukrishnan7Philip Cherian8X. Eric Hu9Charles E. McKenna10Frank H. Ebetino11Shuting Sun12Edward M. Schwarz13Chao Xie14Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USACenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USACenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USACenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USACenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USACenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USACenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USACenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USABioVinc, LLC, Pasadena, CA 91107, USABioVinc, LLC, Pasadena, CA 91107, USADepartment of Chemistry, University of Southern California, Los Angeles, CA 90089, USABioVinc, LLC, Pasadena, CA 91107, USABioVinc, LLC, Pasadena, CA 91107, USACenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USACenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USAThe use of local antibiotics to treat bone infections has been questioned due to a lack of clinical efficacy and emerging information about <i>Staphylococcus aureus</i> 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 <i>S. aureus</i> 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 <i>O</i>-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 (<i>p</i> < 0.001). In contrast, the less labile tedizolid <i>N</i>-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 <i>S. aureus</i> biofilm on OLCN bone surfaces and support in vivo drug development of a sitafloxacin BCA.https://www.mdpi.com/2079-6382/10/6/732osteomyelitis<i>Staphylococcus aureus</i>antibioticbisphosphonatescanning electron microscopy |
| spellingShingle | Emmanuela Adjei-Sowah Yue Peng Jason Weeks Jennifer H. Jonason Karen L. de Mesy Bentley Elysia Masters Yugo Morita Gowrishankar Muthukrishnan Philip Cherian X. Eric Hu Charles E. McKenna Frank H. Ebetino Shuting Sun Edward M. Schwarz Chao Xie Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and Tedizolid Antibiotics osteomyelitis <i>Staphylococcus aureus</i> antibiotic bisphosphonate scanning electron microscopy |
| 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 | osteomyelitis <i>Staphylococcus aureus</i> antibiotic bisphosphonate scanning electron microscopy |
| url | https://www.mdpi.com/2079-6382/10/6/732 |
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