Substituted diphenyl ethers as a broad-spectrum platform for the development of chemotherapeutics for the treatment of tularaemia
Substituted diphenyl ethers as a broad-spectrum platform for the development of chemotherapeutics for the treatment of tularaemia
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DOI：
10.1093/jac/dkp307
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发表时间：
2009-11-01
影响因子：
5.2
通讯作者：
Slayden, Richard A.
中科院分区：
文献类型：
--
作者：
England, Kathleen;Ende, Christopher Am;Slayden, Richard A.
目的：国家过敏和传染病研究所将土拉热弗朗西斯菌列为A类优先病原体。尽管有治疗土拉菌病的药物，但自然感染的死亡率仍接近30%。此外，由于毒性和输送方面的问题，现有药物用于治疗接触或预防的效用有限。本研究的目的是评估铅烷基取代二苯醚，SBPT 04，在F。方法：通过腹腔（ip）和口服（po）途径递送SBPT 04，并监测小鼠的发病率、死亡率和疾病复发。进行药代动力学研究以评价生物利用度。结果：SBPT 04是一种有效的烯酰-ACP还原酶ftuFabl的抑制剂，对F.当通过IP和PO途径两者递送时，在感染的鼠模型中的土拉菌。SBPT 04经ip给药在治疗第4天清除感染，而SBPT 04经po给药导致延迟传播。重要的是，ip或po递送的SBPT 04证明了功效，没有疾病复发的迹象。药代动力学研究表明，与口服给药相比，腹腔给药后血药浓度增加，与观察到的100%的存活率相关。结论：除了作为一个有效的先导药物外，这项工作证实了取代二苯醚作为开发新的广谱化疗药物的平台。土拉热。
Objectives: The National Institute of Allergy and Infectious Disease classifies Francisella tularensis as a Category A priority pathogen. Despite the availability of drugs for treating tularaemia, the mortality in naturally acquired cases can still approach 30%. In addition, the usefulness of existing drugs for treatment in response to exposure or for prophylaxis is limited because of toxicity and delivery concerns. The aim of this study was to assess the efficacy of the lead alkyl-substituted diphenyl ether, SBPT04, in the F. tularensis murine model of infection.Methods: SBPT04 was delivered by intraperitoneal (ip) and oral (po) routes, and mice were monitored for morbidity, mortality and relapse of disease. Pharmacokinetic studies were performed to evaluate bioavailability. Phase I and Phase II metabolism of SBPT04 was assessed in mouse and human microsomes.Results: SBPT04, a potent inhibitor of the enoyl-ACP reductase enzyme ftuFabl, has efficacy against F. tularensis in the murine model of infection when delivered by both ip and po routes. SBPT04 delivered ip cleared infection by day 4 of treatment, and SBPT04 delivered po resulted in delayed dissemination. Importantly, SBPT04 delivered ip or po demonstrated efficacy with no signs of relapse of disease. Pharmacokinetic studies show increased serum concentrations following ip delivery compared with po delivery, which correlates with the observed survival rate of 100%.Conclusions: In addition to being a potent lead, this work substantiates substituted diphenyl ethers as a platform for the development of novel broad-spectrum chemotherapeutics to other bacterial agents in addition to F. tularensis.