title: In Vivo Activity of the Benzothiazinones PBTZ169 and BTZ043 against Nocardia brasiliensis.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratorio Interdisciplinario de Investigación Dermatológica, Servicio de Dermatología, Hospital Universitario "Dr. José Eleuterio González", Monterrey, Nuevo León, México.
authors.forename: Norma Alejandra
authors.initials: NA
authors.lastname: González-Martínez
authors.affiliation: Centro de Investigación Biomédica del Noreste, IMSS, Monterrey, Nuevo León, México.
authors.forename: Hector Gerardo
authors.initials: HG
authors.lastname: Lozano-Garza
authors.affiliation: Centro de Investigación Biomédica del Noreste, IMSS, Monterrey, Nuevo León, México.
authors.forename: Jorge
authors.initials: J
authors.lastname: Castro-Garza
authors.affiliation: Laboratorio Interdisciplinario de Investigación Dermatológica, Servicio de Dermatología, Hospital Universitario "Dr. José Eleuterio González", Monterrey, Nuevo León, México.
authors.forename: Alexandra
authors.initials: A
authors.lastname: De Osio-Cortez
authors.affiliation: Centro de Investigación Biomédica del Noreste, IMSS, Monterrey, Nuevo León, México.
authors.forename: Javier
authors.initials: J
authors.lastname: Vargas-Villarreal
authors.affiliation: Departamento de Química Analítica de la Facultad de Medicina de la UANL, Monterrey, Nuevo León, México.
authors.forename: Norma
authors.initials: N
authors.lastname: Cavazos-Rocha
authors.affiliation: Laboratorio Interdisciplinario de Investigación Dermatológica, Servicio de Dermatología, Hospital Universitario "Dr. José Eleuterio González", Monterrey, Nuevo León, México.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ocampo-Candiani
authors.affiliation: Bakh Institute of Biochemistry, Russian Academy of Science, Moscow, Russia.
authors.forename: Vadim
authors.initials: V
authors.lastname: Makarov
authors.affiliation: Global Health Institute, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
authors.affiliation: Laboratorio Interdisciplinario de Investigación Dermatológica, Servicio de Dermatología, Hospital Universitario "Dr. José Eleuterio González", Monterrey, Nuevo León, México.
authors.forename: Lucio
authors.initials: L
authors.lastname: Vera-Cabrera
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008271:Mycetoma / Q000188:drug therapy; D009615:Nocardia / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*; D013843:Thiazines / Q000494:pharmacology*
chemical_list: C540716:2-(2-methyl-1,4-dioxa-8-azaspiro(4.5)dec-8-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one; D010879:Piperazines; D013141:Spiro Compounds; D013843:Thiazines; C000592783:macozinone