Citation

Pathogens and pathogenic agents such as lethal toxin, exploit host proteins for their success. Antibiotic discovery efforts have been focused on developing drugs that selectively target pathogens, despite the potential for drug resistance and providing no guarantee of fewer side effects for the patient. This dissertation describes the systematic efforts to identify drugs that alter those host proteins that are involved in the anthrax toxin internalization pathway. Anthrax is a rare and lethal disease caused by the toxin producing, gram-positive bacterium, Bacillus anthracis. The lethality of anthrax is largely attributed to the toxins that circulate within the host, destroying host tissues as well as the immune system, thus hampering host efforts to destroy the bacteria. Drug candidates were identified through cellular and protein-based screens using a drug library comprised of previously approved and off-patent drugs. Such a library creates the potential for identifying therapies for new indications, while potentially reducing the time and capital necessary for regulatory approval. We have successfully identified an anthrax antitoxin drug that interferes with host Cathepsin B, a lysosomal protein necessary for authophagic flux. On the observation that Cathepsin B is necessary for the success of other pathogenic agents, we demonstrated that our drug hit could prevent other infections, such as Ebola. Subsequent screens were designed to optimize the search for broad-spectrum therapies that interfere with those host proteins involved in the anthrax toxin internalization pathway but which play a role in internalizing other pathogenic agents such as Pseudomonas exotoxin A, Cholera, and Diphtheria toxin. We were able to identify a drug that inhibits host caspases, proteases involved in programmed cell death, and showed that this drug was a successful broad-spectrum therapy for Zika virus. Finally we aimed to indentify drugs that could simultaneously interfere with host proteins and anthrax lethal toxin, and identified two drugs. Drug optimization and drug combinations based on our host-oriented and broad-spectrum identification methods could provide for more effective and better-tolerated therapies for patients suffering from infectious diseases.