TY - JOUR
T1 - In Vivo Activity of Repurposed Amodiaquine as a Host-Targeting Therapy for the Treatment of Anthrax
AU - Martchenko Shilman, Mikhail
AU - Bartolo, Gloria
AU - Alameh, Saleem
AU - Peterson, Johnny W.
AU - Lawrence, William S.
AU - Peel, Jennifer E.
AU - Sivasubramani, Satheesh K.
AU - Beasley, David W.C.
AU - Cote, Christopher K.
AU - Demons, Samandra T.
AU - Halasahoris, Stephanie A.
AU - Miller, Lynda L.
AU - Klimko, Christopher P.
AU - Shoe, Jennifer L.
AU - Fetterer, David P.
AU - McComb, Ryan
AU - Ho, Chi Lee C.
AU - Bradley, Kenneth A.
AU - Hartmann, Stella
AU - Cheng, Luisa W.
AU - Chugunova, Marina
AU - Kao, Chiu Yen
AU - Tran, Jennifer K.
AU - Derbedrossian, Aram
AU - Zilbermintz, Leeor
AU - Amali-Adekwu, Emiene
AU - Levitin, Anastasia
AU - West, Joel
N1 - Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.
PY - 2021/8/13
Y1 - 2021/8/13
N2 - 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.
AB - 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.
KW - Bacillus anthracis
KW - amodiaquine
KW - anthrax toxin
KW - efficacy
KW - pharmacokinetics
KW - safety
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U2 - 10.1021/acsinfecdis.1c00190
DO - 10.1021/acsinfecdis.1c00190
M3 - Article
C2 - 34218660
AN - SCOPUS:85111026585
SN - 2373-8227
VL - 7
SP - 2176
EP - 2191
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 8
ER -