Cell division inhibitors with efficacy equivalent to isoniazid in the acute murine Mycobacterium tuberculosis infection model.
Cell division inhibitors with efficacy equivalent to isoniazid in the acute murine Mycobacterium tuberculosis infection model.
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DOI：
10.1093/jac/dkv226
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发表时间：
2015-11
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通讯作者：
Susan E. Knudson;D. Awasthi;Kunal Kumar;A. Carreau;L. Goullieux;S. Lagrange;Hélène Vermet;I. Ojima;R. Slayden
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文献类型：
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作者：
Susan E. Knudson;D. Awasthi;Kunal Kumar;A. Carreau;L. Goullieux;S. Lagrange;Hélène Vermet;I. Ojima;R. Slayden
对一种或多种一线结核病药物耐药的临床菌株数量不断增加，使这种疾病的管理复杂化。为了开发具有改进功效的下一代基于苯并咪唑的FtsZ抑制剂，我们采用了基于全细菌效力、杀菌活性、血浆和代谢稳定性以及体内功效研究的迭代优化策略。方法评价候选苯并咪唑对结核分枝杆菌H37 Rv和选择的临床菌株的效力、对Vero细胞的毒性以及在血浆和肝微粒体中的化合物稳定性。在急性小鼠M.结核感染模型通过腹膜内和口服途径。结果SB-P17 G-A33、SB-P17 G-A38和SB-P17 G-A42对M.结核H37 Rv和临床筛选菌株的平均浓度为0.18- 0.39mg/L。SB-P17 G-A38和SB-P17 G-A42以50 mg/kg每日两次腹膜内或口服递送，证明了在肺中将细菌负荷降低5.7-6.3 log 10 cfu和在脾中降低3.9-5.0 log 10 cfu的功效。SB-P17 G-A33以50 mg/kg每日两次腹腔内或口服给药也使肺中的细菌负荷减少1.7-2.1 log 10 cfu，脾中的细菌负荷减少2.5-3.4 log 10 cfu。结论：新一代苯并咪唑类药物具有良好的抗M。结核病已经发展。这是第一份关于苯并咪唑类FtsZ抑制剂的报告，在急性小鼠M.结核病感染模型
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.