title: Small-molecule inhibitors of lethal factor protease activity protect against anthrax infection.
abstract: Bacillus anthracis, the causative agent of anthrax, manifests its pathogenesis through the action of two secreted toxins. The bipartite lethal and edema toxins, a combination of lethal factor or edema factor with the protein protective antigen, are important virulence factors for this bacterium. We previously developed small-molecule inhibitors of lethal factor proteolytic activity (LFIs) and demonstrated their in vivo efficacy in a rat lethal toxin challenge model. In this work, we show that these LFIs protect against lethality caused by anthrax infection in mice when combined with subprotective doses of either antibiotics or neutralizing monoclonal antibodies that target edema factor. Significantly, these inhibitors provided protection against lethal infection when administered as a monotherapy. As little as two doses (10 mg/kg) administered at 2 h and 8 h after spore infection was sufficient to provide a significant survival benefit in infected mice. Administration of LFIs early in the infection was found to inhibit dissemination of vegetative bacteria to the organs in the first 32 h following infection. In addition, neutralizing antibodies against edema factor also inhibited bacterial dissemination with similar efficacy. Together, our findings confirm the important roles that both anthrax toxins play in establishing anthrax infection and demonstrate the potential for small-molecule therapeutics targeting these proteins.
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. mmoayeri@niaid.nih.gov
authors.forename: Mahtab
authors.initials: M
authors.lastname: Moayeri
authors.forename: Devorah
authors.initials: D
authors.lastname: Crown
authors.forename: Guan-Sheng
authors.initials: GS
authors.lastname: Jiao
authors.forename: Seongjin
authors.initials: S
authors.lastname: Kim
authors.forename: Alan
authors.initials: A
authors.lastname: Johnson
authors.forename: Clinton
authors.initials: C
authors.lastname: Leysath
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
mesh_terms: D000818:Animals; D000881:Anthrax / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D000942:Antigens, Bacterial; D001408:Bacillus anthracis / Q000187:drug effects* / Q000254:growth & development; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D004334:Drug Administration Schedule; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013171:Spores, Bacterial / Q000187:drug effects* / Q000254:growth & development; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D057134:Antibodies, Neutralizing; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D011480:Protease Inhibitors; C030325:anthrax toxin