In Vivo Activity of Repurposed Amodiaquine as a Host-Targeting Therapy for the Treatment of Anthrax

Mikhail Martchenko Shilman, Gloria Bartolo, Saleem Alameh, Johnny Peterson, William S. Lawrence, Jennifer E. Peel, Satheesh K. Sivasubramani, David W.C. Beasley, Christopher K. Cote, Samandra T. Demons, Stephanie A. Halasahoris, Lynda L. Miller, Christopher P. Klimko, Jennifer L. Shoe, David P. Fetterer, Ryan McComb, Chi Lee C. Ho, Kenneth A. Bradley, Stella Hartmann, Luisa W. ChengMarina Chugunova, Chiu Yen Kao, Jennifer K. Tran, Aram Derbedrossian, Leeor Zilbermintz, Emiene Amali-Adekwu, Anastasia Levitin, Joel West

Research output: Contribution to journalArticlepeer-review

Abstract

Anthrax is caused by Bacillus anthracis and can result in nearly 100% mortality due in part to anthrax toxin. Antimalarial amodiaquine (AQ) acts as a host-oriented inhibitor of anthrax toxin endocytosis. Here, we determined the pharmacokinetics and safety of AQ in mice, rabbits, and humans as well as the efficacy in the fly, mouse, and rabbit models of anthrax infection. In the therapeutic-intervention studies, AQ nearly doubled the survival of mice infected subcutaneously with a B. anthracis dose lethal to 60% of the animals (LD60). In rabbits challenged with 200 LD50 of aerosolized B. anthracis, AQ as a monotherapy delayed death, doubled the survival rate of infected animals that received a suboptimal amount of antibacterial levofloxacin, and reduced bacteremia and toxemia in tissues. Surprisingly, the anthrax efficacy of AQ relies on an additional host macrophage-directed antibacterial mechanism, which was validated in the toxin-independent Drosophila model of Bacillus infection. Lastly, a systematic literature review of the safety and pharmacokinetics of AQ in humans from over 2 »000 published articles revealed that AQ is likely safe when taken as prescribed, and its pharmacokinetics predicts anthrax efficacy in humans. Our results support the future examination of AQ as adjunctive therapy for the prophylactic anthrax treatment.

Original languageEnglish (US)
Pages (from-to)2176-2191
Number of pages16
JournalACS Infectious Diseases
Volume7
Issue number8
DOIs
StatePublished - Aug 13 2021

Keywords

  • Bacillus anthracis
  • amodiaquine
  • anthrax toxin
  • efficacy
  • pharmacokinetics
  • safety

ASJC Scopus subject areas

  • Infectious Diseases

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