2. Academic Validation
  3. Discovery of D8-03 as an Inhibitor of Intracellular Growth of Francisella tularensis

Discovery of D8-03 as an Inhibitor of Intracellular Growth of Francisella tularensis

  • ACS Infect Dis. 2024 Jun 14. doi: 10.1021/acsinfecdis.4c00116.
Shannon Whiles 1,  Quanzheng Zhang 2,  Zach Chamberlain 1,  Manish K Singh 2,  Shaun Steele 1,  Linda Zheng 2,  Kristin Rosche 3,  Weigang Huang 2,  Huanyao Gao 2,  Qisheng Zhang 2 4,  Thomas Kawula 1
Affiliations

Affiliations

  • 1 Paul G. Allen School for Global Health, Washington State University, Pullman, Washington 99164, United States.
  • 2 Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 3 Program in Vector-borne Disease, Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, Washington 99164, United States.
  • 4 Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
PMID: 38876983 DOI: 10.1021/acsinfecdis.4c00116
Abstract

Francisella tularensis is a Gram-negative facultative intracellular Bacterial pathogen that is classified by the Centers for Disease Control and Prevention as a Tier 1 Select Agent. F. tularensis Infection causes the disease tularemia, also known as rabbit fever. Treatment of tularemia is limited to few effective Antibiotics which are associated with high relapse rates, toxicity, and potential emergence of antibiotic-resistant strains. Consequently, new therapeutic options for tularemia are needed. Through screening a focused chemical library and subsequent structure-activity relationship studies, we have discovered a new and potent inhibitor of intracellular growth of Francisella tularensis, D8-03. Importantly, D8-03 effectively reduces Bacterial burden in mice infected with F. tularensis. Preliminary mechanistic investigations suggest that D8-03 works through a potentially novel host-dependent mechanism and serves as a promising lead compound for further development.

Keywords

Francisella tularensis; antibiotic; cyclodextrin; host-directed therapy; intracellular pathogen; tularemia.

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