Cell division inhibitors with efficacy equivalent to isoniazid in the acute murineMycobacterium tuberculosisinfection model
| العنوان: | Cell division inhibitors with efficacy equivalent to isoniazid in the acute murineMycobacterium tuberculosisinfection model |
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| المؤلفون: | Kunal Kumar, Iwao Ojima, Hélène Vermet, Susan E. Knudson, Alexandra Carreau, Sophie Lagrange, Laurent Goullieux, Richard A. Slayden, Divya Awasthi |
| المصدر: | Journal of Antimicrobial Chemotherapy. 70:3070-3073 |
| بيانات النشر: | Oxford University Press (OUP), 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Microbiology (medical), Tuberculosis, Cell Survival, Antitubercular Agents, Administration, Oral, Spleen, Microbial Sensitivity Tests, Microbiology, Mycobacterium tuberculosis, Mice, Bacterial Proteins, Drug Stability, In vivo, Chlorocebus aethiops, Isoniazid, medicine, Animals, Potency, Pharmacology (medical), Vero Cells, Original Research, Pharmacology, biology, business.industry, medicine.disease, biology.organism_classification, Cytoskeletal Proteins, Disease Models, Animal, Treatment Outcome, Infectious Diseases, medicine.anatomical_structure, Inactivation, Metabolic, Toxicity, Vero cell, Benzimidazoles, business, Cell Division, Injections, Intraperitoneal, medicine.drug |
| الوصف: | OBJECTIVES The increasing number of clinical strains resistant to one or more of the front-line TB drugs complicates the management of this disease. To develop next-generation benzimidazole-based FtsZ inhibitors with improved efficacy, we employed iterative optimization strategies based on whole bacteria potency, bactericidal activity, plasma and metabolic stability and in vivo efficacy studies. METHODS Candidate benzimidazoles were evaluated for potency against Mycobacterium tuberculosis H37Rv and select clinical strains, toxicity against Vero cells and compound stability in plasma and liver microsomes. The efficacy of lead compounds was assessed in the acute murine M. tuberculosis infection model via intraperitoneal and oral routes. RESULTS MICs of SB-P17G-A33, SB-P17G-A38 and SB-P17G-A42 for M. tuberculosis H37Rv and select clinical strains were 0.18-0.39 mg/L. SB-P17G-A38 and SB-P17G-A42 delivered at 50 mg/kg twice daily intraperitoneally or orally demonstrated efficacy in reducing the bacterial load by 5.7-6.3 log10 cfu in the lungs and 3.9-5.0 log10 cfu in the spleen. SB-P17G-A33 delivered at 50 mg/kg twice daily intraperitoneally or orally also reduced the bacterial load by 1.7-2.1 log10 cfu in the lungs and 2.5-3.4 log10 cfu in the spleen. CONCLUSIONS Next-generation benzimidazoles with excellent potency and efficacy against M. tuberculosis have been developed. This is the first report on benzimidazole-based FtsZ inhibitors showing an equivalent level of efficacy to isoniazid in an acute murine M. tuberculosis infection model. |
| تدمد: | 1460-2091 0305-7453 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4d977a30cd4f47639ae1fc8514266d39 https://doi.org/10.1093/jac/dkv226 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....4d977a30cd4f47639ae1fc8514266d39 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602091 03057453 |
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