In Vivo Activity of the Benzothiazinones PBTZ169 and BTZ043 against Nocardia brasiliensis.
BACKGROUND:Mycetoma is a neglected, chronic, and deforming infectious disease caused by fungi and actinomycetes. In Mexico, N. brasiliensis is the predominant etiologic agent. Therapeutic alternatives are necessary because the current drug regimens have several disadvantages. Benzothiazinones (BTZ)...
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ftdoajarticles:oai:doaj.org/article:e12dfe7443fe49478ac9f16457e24abf 2023-05-15T15:13:28+02:00 In Vivo Activity of the Benzothiazinones PBTZ169 and BTZ043 against Nocardia brasiliensis. Norma Alejandra González-Martínez Hector Gerardo Lozano-Garza Jorge Castro-Garza Alexandra De Osio-Cortez Javier Vargas-Villarreal Norma Cavazos-Rocha Jorge Ocampo-Candiani Vadim Makarov Stewart T Cole Lucio Vera-Cabrera 2015-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0004022 https://doaj.org/article/e12dfe7443fe49478ac9f16457e24abf EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4608729?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004022 https://doaj.org/article/e12dfe7443fe49478ac9f16457e24abf PLoS Neglected Tropical Diseases, Vol 9, Iss 10, p e0004022 (2015) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2015 ftdoajarticles https://doi.org/10.1371/journal.pntd.0004022 2022-12-31T00:22:00Z BACKGROUND:Mycetoma is a neglected, chronic, and deforming infectious disease caused by fungi and actinomycetes. In Mexico, N. brasiliensis is the predominant etiologic agent. Therapeutic alternatives are necessary because the current drug regimens have several disadvantages. Benzothiazinones (BTZ) are a new class of candidate drugs that inhibit decaprenyl-phosphoribose-epimerase (DprE1), an essential enzyme involved in the cell wall biosynthesis of Corynebacterineae. METHODOLOGY/PRINCIPAL FINDINGS:In this study, the in vitro activity of the next generation BTZ, PBTZ169, was tested against thirty Nocardia brasiliensis isolates. The MIC50 and MIC90 values for PBTZ169 were 0.0075 and 0.03 μg/mL, respectively. Because Nocardia is a potential intracellular bacterium, a THP-1 macrophage monolayer was infected with N. brasiliensis HUJEG-1 and then treated with PBTZ169, resulting in a decrease in the number of colony-forming units (CFUs) at a concentration of 0.25X the in vitro value. The in vivo activity was evaluated after infecting female BALB/c mice in the right hind food-pad. After 6 weeks, treatment was initiated with PBTZ169 and its activity was compared with the first generation compound, BTZ043. Both BTZ compounds were administered at 100 mg/kg twice daily by gavage, and sulfamethoxazole/trimethoprim (SXT), at 100 mg/kg sulfamethoxazole, was used as a positive control. After 22 weeks of therapy, only PBTZ169 and SXT displayed statistically significant activity. CONCLUSION:These results indicate that DprE1 inhibitors may be useful for treating infections of Nocardia and may therefore be active against other actinomycetoma agents. We must test combinations of these compounds with other antimicrobial agents, such as linezolid, tedizolid or SXT, that have good to excellent in vivo activity, as well as new DprE1 inhibitors that can achieve higher plasma levels. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 9 10 e0004022 |
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Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Norma Alejandra González-Martínez Hector Gerardo Lozano-Garza Jorge Castro-Garza Alexandra De Osio-Cortez Javier Vargas-Villarreal Norma Cavazos-Rocha Jorge Ocampo-Candiani Vadim Makarov Stewart T Cole Lucio Vera-Cabrera In Vivo Activity of the Benzothiazinones PBTZ169 and BTZ043 against Nocardia brasiliensis. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
BACKGROUND:Mycetoma is a neglected, chronic, and deforming infectious disease caused by fungi and actinomycetes. In Mexico, N. brasiliensis is the predominant etiologic agent. Therapeutic alternatives are necessary because the current drug regimens have several disadvantages. Benzothiazinones (BTZ) are a new class of candidate drugs that inhibit decaprenyl-phosphoribose-epimerase (DprE1), an essential enzyme involved in the cell wall biosynthesis of Corynebacterineae. METHODOLOGY/PRINCIPAL FINDINGS:In this study, the in vitro activity of the next generation BTZ, PBTZ169, was tested against thirty Nocardia brasiliensis isolates. The MIC50 and MIC90 values for PBTZ169 were 0.0075 and 0.03 μg/mL, respectively. Because Nocardia is a potential intracellular bacterium, a THP-1 macrophage monolayer was infected with N. brasiliensis HUJEG-1 and then treated with PBTZ169, resulting in a decrease in the number of colony-forming units (CFUs) at a concentration of 0.25X the in vitro value. The in vivo activity was evaluated after infecting female BALB/c mice in the right hind food-pad. After 6 weeks, treatment was initiated with PBTZ169 and its activity was compared with the first generation compound, BTZ043. Both BTZ compounds were administered at 100 mg/kg twice daily by gavage, and sulfamethoxazole/trimethoprim (SXT), at 100 mg/kg sulfamethoxazole, was used as a positive control. After 22 weeks of therapy, only PBTZ169 and SXT displayed statistically significant activity. CONCLUSION:These results indicate that DprE1 inhibitors may be useful for treating infections of Nocardia and may therefore be active against other actinomycetoma agents. We must test combinations of these compounds with other antimicrobial agents, such as linezolid, tedizolid or SXT, that have good to excellent in vivo activity, as well as new DprE1 inhibitors that can achieve higher plasma levels. |
format |
Article in Journal/Newspaper |
author |
Norma Alejandra González-Martínez Hector Gerardo Lozano-Garza Jorge Castro-Garza Alexandra De Osio-Cortez Javier Vargas-Villarreal Norma Cavazos-Rocha Jorge Ocampo-Candiani Vadim Makarov Stewart T Cole Lucio Vera-Cabrera |
author_facet |
Norma Alejandra González-Martínez Hector Gerardo Lozano-Garza Jorge Castro-Garza Alexandra De Osio-Cortez Javier Vargas-Villarreal Norma Cavazos-Rocha Jorge Ocampo-Candiani Vadim Makarov Stewart T Cole Lucio Vera-Cabrera |
author_sort |
Norma Alejandra González-Martínez |
title |
In Vivo Activity of the Benzothiazinones PBTZ169 and BTZ043 against Nocardia brasiliensis. |
title_short |
In Vivo Activity of the Benzothiazinones PBTZ169 and BTZ043 against Nocardia brasiliensis. |
title_full |
In Vivo Activity of the Benzothiazinones PBTZ169 and BTZ043 against Nocardia brasiliensis. |
title_fullStr |
In Vivo Activity of the Benzothiazinones PBTZ169 and BTZ043 against Nocardia brasiliensis. |
title_full_unstemmed |
In Vivo Activity of the Benzothiazinones PBTZ169 and BTZ043 against Nocardia brasiliensis. |
title_sort |
in vivo activity of the benzothiazinones pbtz169 and btz043 against nocardia brasiliensis. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2015 |
url |
https://doi.org/10.1371/journal.pntd.0004022 https://doaj.org/article/e12dfe7443fe49478ac9f16457e24abf |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 9, Iss 10, p e0004022 (2015) |
op_relation |
http://europepmc.org/articles/PMC4608729?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0004022 https://doaj.org/article/e12dfe7443fe49478ac9f16457e24abf |
op_doi |
https://doi.org/10.1371/journal.pntd.0004022 |
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PLOS Neglected Tropical Diseases |
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9 |
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10 |
container_start_page |
e0004022 |
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