Substituted diphenyl ethers as a broad-spectrum platform for the development of chemotherapeutics for the treatment of tularaemia.

The Journal of Antimicrobial Chemotherapy
Kathleen EnglandRichard A Slayden

Abstract

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. 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. SBPT04, a potent inhibitor of the enoyl-ACP reductase enzyme ftuFabI, 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 diseas...Continue Reading

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Citations

Mar 12, 2011·The Journal of Antimicrobial Chemotherapy·Nina LiuPeter J Tonge
Oct 3, 2012·PloS One·Claudia R MolinsJeannine M Petersen
Sep 14, 2014·European Journal of Medicinal Chemistry·Hui WangPeter J Tonge
Jan 31, 2015·Journal of Chemical Information and Modeling·Alexander L PerrymanArthur J Olson

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