Protein Secretion as a Novel Drug Target for Tuberculosis
Abstract
Topic Area: This project relates to Fiscal Year 2018 Peer Reviewed Medical Research Program Topic Areas “Tuberculosis” and “Antimicrobial Resistance.” The proposal addresses the Area of Encouragement “Tuberculosis.” Our work addresses “Research to understand, diagnose, or treat multidrug-resistant tuberculosis or extensively drug-resistant tuberculosis.” Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a major human pathogen causing significant human suffering worldwide, with 1.8 million deaths and 10.4 million new cases in 2016. TB is of significant concern to the military since TB is contagious and units are regularly deployed to areas where TB is endemic. Although effective drug regimens for the treatment of TB exist, they are lengthy (>6 months), involve multiple antibiotics to achieve sterilization and prevent relapse, and can have side effects that negatively impact personnel. There is an urgent unmet need for new therapeutic agents and an increased understanding of the disease process. We propose to develop anti-tubercular agents that work in new ways by targeting protein secretion, a key virulence mechanism, and to understand how these compounds kill bacteria. Protein secretion is the mechanism by which bacteria excrete or export proteins from inside the cell to the outside; it is important for both the survival of M. tuberculosis and for its ability to cause disease. Disrupting this mechanism could lead to new drugs to treat TB in people. We have tested >70,000 compounds for their ability to prevent the growth of M. tuberculosis in the laboratory. We identified a number of compounds with good activity and that are likely to work by interfering with protein secretion. The aim of this proposal is to develop new drug candidates from these molecules and in parallel to determine how the molecules work in killing the bacteria. The outcomes of this proposal would be advanced lead candidates ready for preclinical testing, an increased knowledge of how protein secretion can be disrupted, and further validation of protein secretion as a drug target.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910321
Entities
People
- Tanya Parish
Organizations
- Infectious Disease Research Institute
- United States Army