Small-Molecule Inhibitors of Lethal Factor Protease Activity Protect against Anthrax Infection
Small-Molecule Inhibitors of Lethal Factor Protease Activity Protect against Anthrax Infection
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DOI：
10.1128/aac.00941-13
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发表时间：
2013-09-01
影响因子：
4.9
通讯作者：
Leppla, Stephen H.
中科院分区：
文献类型：
--
作者：
Moayeri, Mahtab;Crown, Devorah;Leppla, Stephen H.
炭疽杆菌是炭疽的病原体，通过两种分泌毒素的作用来表现其发病机制。两部致死性和水肿性毒素，是致死性因子或水肿性因子与蛋白质保护性抗原的组合，是该细菌的重要毒力因子。我们之前开发了致死因子蛋白水解活性（LFIs）的小分子抑制剂，并在大鼠致死毒素攻击模型中证明了它们的体内功效。在这项工作中，我们表明，当与亚保护剂量的抗生素或靶向水肿因子的中和单克隆抗体联合使用时，这些lfi可以保护小鼠免受炭疽感染引起的死亡。值得注意的是，这些抑制剂作为单一疗法提供了对致命感染的保护。在孢子感染后2小时和8小时给予两次剂量（10 mg/kg）足以为感染小鼠提供显着的生存益处。发现在感染早期给予lfi可抑制感染后32小时内营养细菌向器官的传播。此外，抗水肿因子的中和抗体也具有类似的抑制细菌传播的功效。总之，我们的研究结果证实了这两种炭疽毒素在建立炭疽感染中发挥的重要作用，并展示了针对这些蛋白质的小分子治疗的潜力。
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.