JAC Advance Access originally published online on September 4, 2009
Journal of Antimicrobial Chemotherapy 2009 64(5):1052-1061; doi:10.1093/jac/dkp307
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Original research |
Substituted diphenyl ethers as a broad-spectrum platform for the development of chemotherapeutics for the treatment of tularaemia
1 Rocky Mountain Regional Center of Excellence, Colorado State University, Fort Collins, CO, USA 2 Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA 3 Institute of Chemical Biology and Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, NY, USA 4 Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, USA 5 Department of Bioagricultural Sciences and Pest Management, Colorado State University, Fort Collins, CO, USA
Received 26 February 2009; returned 1 June 2009; revised 14 July 2009; accepted 29 July 2009
* Corresponding author. Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-2025, USA. Tel: +1-970-491-2902; Fax: +1-970-491-1815; E-mail: richard.slayden{at}colostate.edu
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 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 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.
Keywords: Francisella tularensis , fatty acid , FabI , efficacy , mouse model
Deceased.