TunR2, a novel mode-of-action tunicamycin-type antibiotic : Pharmacokinetics in C57BL/6 mouse and Holstein cattle
We have investigated the pharmacokinetics of TunR2, a modified tunicamycin-type antibiotic, in mice and cattle. TunR2 has previously been shown to be effective in a mycobacterial disease model using zebrafish, with a minimal activation of the eukaryotic unfolded protein response (upr) and a reductio...
| Autores principales: | , , , , |
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| Formato: | info:ar-repo/semantics/artículo |
| Lenguaje: | Inglés |
| Publicado: |
Public Library of Science
2025
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| Materias: | |
| Acceso en línea: | http://hdl.handle.net/20.500.12123/23447 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0327932 https://doi.org/10.1371/journal.pone.0327932 |
| _version_ | 1855038757721341952 |
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| author | Colombatti Olivieri, Maria Alejandra Cassmann, Eric D. Jackson, Michael A. Price, Neil P. J. Bannantine, John P. |
| author_browse | Bannantine, John P. Cassmann, Eric D. Colombatti Olivieri, Maria Alejandra Jackson, Michael A. Price, Neil P. J. |
| author_facet | Colombatti Olivieri, Maria Alejandra Cassmann, Eric D. Jackson, Michael A. Price, Neil P. J. Bannantine, John P. |
| author_sort | Colombatti Olivieri, Maria Alejandra |
| collection | INTA Digital |
| description | We have investigated the pharmacokinetics of TunR2, a modified tunicamycin-type antibiotic, in mice and cattle. TunR2 has previously been shown to be effective in a mycobacterial disease model using zebrafish, with a minimal activation of the eukaryotic unfolded protein response (upr) and a reduction in the in vivo mycobacterial burden. In this study, we presented statistically relevant pharmacokinetics of native tunicamycin (Tun) and two less toxic modified analogs, TunR2 and TunR1, using a well-defined clonal C57BL/6 mouse (both male and female). Blood samples were collected at multiple time points, and plasma concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were calculated using a two-compartment analysis. Our findings indicate that Tun and TunR1 tend to distribute in tissue compared to TunR2, which has a longer half-life than Tun. This translates into longer TunR2 activity time, potentially allowing for less frequent dosing than Tun or TunR1. We subsequently administered the modified TunR2 to Holstein cattle using a three-bolus intravenous regimen. We monitored blood, milk, urine, and feces over 90 days. In dairy cattle, the pharmacokinetics of TunR2 appear to be cumulative, and clear after 10 days. These findings provide critical new insights into the pharmacokinetics of TunR2. We concluded that TunR2 has considerable potential for treating bacterial infections, particularly as an antimicrobial adjuvant with well-established β-lactam antibiotics. Further studies are required to study safety and optimize dosing regimens for effective therapeutic use, as well as in combination with other antibiotics, such as β-lactams. |
| format | info:ar-repo/semantics/artículo |
| id | INTA23447 |
| institution | Instituto Nacional de Tecnología Agropecuaria (INTA -Argentina) |
| language | Inglés |
| publishDate | 2025 |
| publishDateRange | 2025 |
| publishDateSort | 2025 |
| publisher | Public Library of Science |
| publisherStr | Public Library of Science |
| record_format | dspace |
| spelling | INTA234472025-08-18T10:19:30Z TunR2, a novel mode-of-action tunicamycin-type antibiotic : Pharmacokinetics in C57BL/6 mouse and Holstein cattle Colombatti Olivieri, Maria Alejandra Cassmann, Eric D. Jackson, Michael A. Price, Neil P. J. Bannantine, John P. Antibiotics Pharmacokinetics Mycobacterium Infectious Diseases Antimicrobials Mice Antibióticos Farmacocinética Enfermedades Infecciosas Antimicrobianos Ratón Holstein Cattle Ganado Holstein We have investigated the pharmacokinetics of TunR2, a modified tunicamycin-type antibiotic, in mice and cattle. TunR2 has previously been shown to be effective in a mycobacterial disease model using zebrafish, with a minimal activation of the eukaryotic unfolded protein response (upr) and a reduction in the in vivo mycobacterial burden. In this study, we presented statistically relevant pharmacokinetics of native tunicamycin (Tun) and two less toxic modified analogs, TunR2 and TunR1, using a well-defined clonal C57BL/6 mouse (both male and female). Blood samples were collected at multiple time points, and plasma concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were calculated using a two-compartment analysis. Our findings indicate that Tun and TunR1 tend to distribute in tissue compared to TunR2, which has a longer half-life than Tun. This translates into longer TunR2 activity time, potentially allowing for less frequent dosing than Tun or TunR1. We subsequently administered the modified TunR2 to Holstein cattle using a three-bolus intravenous regimen. We monitored blood, milk, urine, and feces over 90 days. In dairy cattle, the pharmacokinetics of TunR2 appear to be cumulative, and clear after 10 days. These findings provide critical new insights into the pharmacokinetics of TunR2. We concluded that TunR2 has considerable potential for treating bacterial infections, particularly as an antimicrobial adjuvant with well-established β-lactam antibiotics. Further studies are required to study safety and optimize dosing regimens for effective therapeutic use, as well as in combination with other antibiotics, such as β-lactams. Instituto de Biotecnología Fil: Colombatti Olivieri, Maria Alejandra. United States Department of Agriculture (USDA). Agricultural Research Service (ARS). National Animal Disease Center; Estados Unidos Fil: Colombatti Olivieri, Maria Alejandra. Agricultural Research Service Participation Program. Oak Ridge Institute for Science and Education (ORISE); Estados Unidos Fil: Colombatti Olivieri, Maria Alejandra. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Agrobiotecnología y Biología Molecular; Argentina Fil: Colombatti Olivieri, Maria Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Cassmann, Eric D. United States Department of Agriculture (USDA). Agricultural Research Service (ARS). National Animal Disease Center; Estados Unidos Fil: Jackson, Michael A. United States Department of Agriculture (USDA). Agricultural Research Service (ARS). National Center for Agricultural Utilization Research; Estados Unidos Fil: Price, Neil P. J. United States Department of Agriculture (USDA). Agricultural Research Service (ARS). National Center for Agricultural Utilization Research; Estados Unidos Fil: Bannantine, John P. United States Department of Agriculture (USDA). Agricultural Research Service (ARS). National Animal Disease Center; Estados Unidos 2025-08-18T10:15:48Z 2025-08-18T10:15:48Z 2025-07 info:ar-repo/semantics/artículo info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://hdl.handle.net/20.500.12123/23447 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0327932 1932-6203 https://doi.org/10.1371/journal.pone.0327932 eng info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-sa/4.0/ Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) application/pdf Public Library of Science PLoS One 20 (7) : e0327932 (July 2025) |
| spellingShingle | Antibiotics Pharmacokinetics Mycobacterium Infectious Diseases Antimicrobials Mice Antibióticos Farmacocinética Enfermedades Infecciosas Antimicrobianos Ratón Holstein Cattle Ganado Holstein Colombatti Olivieri, Maria Alejandra Cassmann, Eric D. Jackson, Michael A. Price, Neil P. J. Bannantine, John P. TunR2, a novel mode-of-action tunicamycin-type antibiotic : Pharmacokinetics in C57BL/6 mouse and Holstein cattle |
| title | TunR2, a novel mode-of-action tunicamycin-type antibiotic : Pharmacokinetics in C57BL/6 mouse and Holstein cattle |
| title_full | TunR2, a novel mode-of-action tunicamycin-type antibiotic : Pharmacokinetics in C57BL/6 mouse and Holstein cattle |
| title_fullStr | TunR2, a novel mode-of-action tunicamycin-type antibiotic : Pharmacokinetics in C57BL/6 mouse and Holstein cattle |
| title_full_unstemmed | TunR2, a novel mode-of-action tunicamycin-type antibiotic : Pharmacokinetics in C57BL/6 mouse and Holstein cattle |
| title_short | TunR2, a novel mode-of-action tunicamycin-type antibiotic : Pharmacokinetics in C57BL/6 mouse and Holstein cattle |
| title_sort | tunr2 a novel mode of action tunicamycin type antibiotic pharmacokinetics in c57bl 6 mouse and holstein cattle |
| topic | Antibiotics Pharmacokinetics Mycobacterium Infectious Diseases Antimicrobials Mice Antibióticos Farmacocinética Enfermedades Infecciosas Antimicrobianos Ratón Holstein Cattle Ganado Holstein |
| url | http://hdl.handle.net/20.500.12123/23447 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0327932 https://doi.org/10.1371/journal.pone.0327932 |
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