1. Cell division inhibitors with efficacy equivalent to isoniazid in the acute murine Mycobacterium tuberculosis infection model.
- Author
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Knudson SE, Awasthi D, Kumar K, Carreau A, Goullieux L, Lagrange S, Vermet H, Ojima I, and Slayden RA
- Subjects
- Administration, Oral, Animals, Antitubercular Agents pharmacology, Bacterial Proteins antagonists & inhibitors, Benzimidazoles pharmacology, Cell Division drug effects, Cell Survival drug effects, Chlorocebus aethiops, Cytoskeletal Proteins antagonists & inhibitors, Disease Models, Animal, Drug Stability, Inactivation, Metabolic, Injections, Intraperitoneal, Isoniazid pharmacology, Mice, Microbial Sensitivity Tests, Treatment Outcome, Vero Cells, Antitubercular Agents administration & dosage, Benzimidazoles administration & dosage, Isoniazid administration & dosage, Mycobacterium tuberculosis drug effects, Tuberculosis drug therapy
- Abstract
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., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2015
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