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Antimicrobial Agents and Chemotherapy, September 2005, p. 3875-3882, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3875-3882.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Protection from Anthrax Toxin-Mediated Killing of Macrophages by the Combined Effects of Furin Inhibitors and Chloroquine

Tomoko Komiyama,1 Joel A. Swanson,2 and Robert S. Fuller1*

Departments of Biological Chemistry,1 Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 481092

Received 2 February 2005/ Returned for modification 24 March 2005/ Accepted 22 June 2005

Cell surface proteolytic processing of anthrax protective antigen by furin or other furin-related proteases is required for its oligomerization, endocytosis, and function as a translocon for anthrax lethal and edema factors. Countering toxin lethality is essential to developing effective chemotherapies for anthrax infections that have proceeded beyond the stage at which antibiotics are effective. The primary target for toxin is the macrophage, which can be killed by lethal factor via both necrotic and apoptotic pathways. Here we show that three high-affinity inhibitors of furin efficiently blocked killing of murine J774A.1 macrophages by recombinant protective antigen plus lethal factor: RRD-eglin and RRDG-eglin, developed by engineering the protein protease inhibitor eglin c, and the peptide boronic acid inhibitor acetyl-Arg-Glu-Lys-boroArg pinanediol. Inhibition of killing was dose dependent and correlated with prevention of protective antigen processing. Previous studies have shown that weak bases, such as chloroquine, which neutralize acidic compartments, also interfere with toxin-dependent killing. Here we show that combining furin inhibitors and chloroquine strongly augments the inhibition of toxin-dependent killing, suggesting that combined use of antifurin drugs and chloroquine might provide enhanced therapeutic benefits. Reversible furin inhibitors protected against anthrax toxin killing for at least 5 h, but by 8 h, toxin-dependent killing resumed even though furin inhibitors were still active. An irreversible chloromethylketone inhibitor did not exhibit this loss of protection.

* Corresponding author. Mailing address: Department of Biological Chemistry, 1301 E. Catherine Road, University of Michigan, Ann Arbor, MI 48109-0606. Phone: (734) 936-9764. Fax: (734) 763-7799. E-mail: bfuller{at}umich.edu.

Antimicrobial Agents and Chemotherapy, September 2005, p. 3875-3882, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3875-3882.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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