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In Vivo Activity of the Benzothiazinones PBTZ169 and BTZ043 against Nocardia brasiliensis.

González-Martínez NA, Lozano-Garza HG, Castro-Garza J, De Osio-Cortez A, Vargas-Villarreal J, Cavazos-Rocha N, Ocampo-Candiani J, Makarov V, Cole ST, Vera-Cabrera L - PLoS Negl Trop Dis (2015)

Bottom Line: 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.After 6 weeks, treatment was initiated with PBTZ169 and its activity was compared with the first generation compound, BTZ043.After 22 weeks of therapy, only PBTZ169 and SXT displayed statistically significant activity.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio Interdisciplinario de Investigación Dermatológica, Servicio de Dermatología, Hospital Universitario "Dr. José Eleuterio González", Monterrey, Nuevo León, México.

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.

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.

No MeSH data available.


Related in: MedlinePlus

Protein sequence alignment of M. tuberculosis H37Rv DprE1 (A) and two orthologs in the genome of N. brasiliensis HUJEG-1.In red, we show Cys387. B: N. brasiliensis YP_006807368 has 97% query cover and 62% identity to MTB DprE1. C: N. brasiliensis YP_006805098, presents a 99% query cover and 74% identity to MTB DprE1.
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pntd.0004022.g006: Protein sequence alignment of M. tuberculosis H37Rv DprE1 (A) and two orthologs in the genome of N. brasiliensis HUJEG-1.In red, we show Cys387. B: N. brasiliensis YP_006807368 has 97% query cover and 62% identity to MTB DprE1. C: N. brasiliensis YP_006805098, presents a 99% query cover and 74% identity to MTB DprE1.

Mentions: The susceptibility of M. tuberculosis DprE1 depends on the covalent binding of BTZ drugs to Cys387, and drug resistance results from the replacement of Cys387 by serine or alanine [5]. Our comparison of the sequence of DprE1 from M. tuberculosis with the genomes of Nocardia revealed that the majority of Nocardia spp. associated with human disease possesses dprE1 orthologs with a cysteine at this position (Fig 5). Comparison of the M. tuberculosis DprE1 protein sequence with N. brasiliensis HUJEG-1 revealed the presence of two proteins, YP_006805098, with 99% query cover and 74% identity, and YP_006807368, with 97% query cover and 62% identity. However, the latter protein possesses a serine instead of a cysteine at position 368 (Fig 6). In N. cyriacigeorgica GUH-2 and N. farcinica IFM 10152, we found only one protein similar to MTB DprE1.


In Vivo Activity of the Benzothiazinones PBTZ169 and BTZ043 against Nocardia brasiliensis.

González-Martínez NA, Lozano-Garza HG, Castro-Garza J, De Osio-Cortez A, Vargas-Villarreal J, Cavazos-Rocha N, Ocampo-Candiani J, Makarov V, Cole ST, Vera-Cabrera L - PLoS Negl Trop Dis (2015)

Protein sequence alignment of M. tuberculosis H37Rv DprE1 (A) and two orthologs in the genome of N. brasiliensis HUJEG-1.In red, we show Cys387. B: N. brasiliensis YP_006807368 has 97% query cover and 62% identity to MTB DprE1. C: N. brasiliensis YP_006805098, presents a 99% query cover and 74% identity to MTB DprE1.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608729&req=5

pntd.0004022.g006: Protein sequence alignment of M. tuberculosis H37Rv DprE1 (A) and two orthologs in the genome of N. brasiliensis HUJEG-1.In red, we show Cys387. B: N. brasiliensis YP_006807368 has 97% query cover and 62% identity to MTB DprE1. C: N. brasiliensis YP_006805098, presents a 99% query cover and 74% identity to MTB DprE1.
Mentions: The susceptibility of M. tuberculosis DprE1 depends on the covalent binding of BTZ drugs to Cys387, and drug resistance results from the replacement of Cys387 by serine or alanine [5]. Our comparison of the sequence of DprE1 from M. tuberculosis with the genomes of Nocardia revealed that the majority of Nocardia spp. associated with human disease possesses dprE1 orthologs with a cysteine at this position (Fig 5). Comparison of the M. tuberculosis DprE1 protein sequence with N. brasiliensis HUJEG-1 revealed the presence of two proteins, YP_006805098, with 99% query cover and 74% identity, and YP_006807368, with 97% query cover and 62% identity. However, the latter protein possesses a serine instead of a cysteine at position 368 (Fig 6). In N. cyriacigeorgica GUH-2 and N. farcinica IFM 10152, we found only one protein similar to MTB DprE1.

Bottom Line: 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.After 6 weeks, treatment was initiated with PBTZ169 and its activity was compared with the first generation compound, BTZ043.After 22 weeks of therapy, only PBTZ169 and SXT displayed statistically significant activity.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio Interdisciplinario de Investigación Dermatológica, Servicio de Dermatología, Hospital Universitario "Dr. José Eleuterio González", Monterrey, Nuevo León, México.

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.

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.

No MeSH data available.


Related in: MedlinePlus