Evaluation of the Protective Effects of Quinacrine Against Bacillus anthracis Ames

Abstract

Bacillus anthracis has gained notoriety as a dangerous biological weapon because of its virulence and ability to produce highly resistant spores. In addition, the ability of this organism to produce plasmid-encoded edema toxin (EdTx) and lethal toxin (LeTx) plays a pivotal role in the pathogenesis of anthrax. In this study, the efficacy of quinacrine was evaluated against the effects of anthrax toxins in vitro and its ability to provide protection against challenge with B. anthracis Ames strain spores in an intranasal mouse and guinea pig model. Quinacrine protected murine macrophages in vitro against cytotoxicity and cAMP production induced by LeTx and EdTx, respectively, at concentrations of 40–80 μM, most likely by preventing acidification of the endosomes. However, animals dosed with human equivalent doses of quinacrine were not protected against respiratory spore challenge. The failure of quinacrine to provide protection against inhalation anthrax was attributed to our inability to attain inhibitory concentrations of the drug in the serum or tissues. After daily administration of 43.3 mg quinacrine to guinea pigs (300 g), serum levels after 96 h were only 9.9 μM, a concentration not sufficient to protect macrophages in vitro. Administration of high doses of quinacrine (86.6 mg/kg) was toxic to the animals. These results illustrate some of the difficulties in developing protective therapeutic strategies against inhalation anthrax even when antitoxic drugs appear effective in vitro.

This work was supported by a grant from the National Institutes of Health (U01AI5385802) and U.S. Army (DAMD170210699). Jason E. Comer, a predoctoral fellow, was supported by National Institutes of Health T32 Predoctoral Training Grants in Emerging and Tropical Infectious Disease (2T32A8007526) and in Biodefense (1T32AI060549). Bacillus anthracis Ames strain was generously provided by C. Richard Lyons at the University of New Mexico Health Science Center, Albuquerque, NM, and duly registered with the Centers for Disease Control (CDC). The authors appreciate the editorial assistance of Mardelle Susman.

Notes

This work was supported by a grant from the National Institutes of Health (U01AI5385802) and U.S. Army (DAMD170210699). Jason E. Comer, a predoctoral fellow, was supported by National Institutes of Health T32 Predoctoral Training Grants in Emerging and Tropical Infectious Disease (2T32A8007526) and in Biodefense (1T32AI060549). Bacillus anthracis Ames strain was generously provided by C. Richard Lyons at the University of New Mexico Health Science Center, Albuquerque, NM, and duly registered with the Centers for Disease Control (CDC). The authors appreciate the editorial assistance of Mardelle Susman.